Odanacatib in the treatment of postmenopausal women with low bone mineral density: Five years of continued therapy in a phase 2 study

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2‐year, phase 2, dose‐ranging trial, postmenopausal women with bone mineral density (BMD) T‐scores ?2.0 to ?3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D₃ and calcium. Prespecified trial‐extensions continued through 5 years. In year 3, all women were re‐randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10–50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus ?0.4% (?3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10–50 mg, n = 26–29), year 5 geometric mean percent changes from baseline in bone resorption markers cross‐linked N‐telopeptide of type I collagen (NTX)/creatinine and cross‐linked C‐telopeptide (CTX) were approximately ?55%, but near baseline for bone formation markers bone‐specific alkaline phosphatase (BSAP) and amino‐terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10–50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well‐tolerated. © 2012 American Society for Bone and Mineral Research.     

Plasmodium falciparum and Plasmodium vivax Genotypes and Efficacy of Intermittent Preventive Treatment in Papua New Guinea

Intermittent preventive treatment of infants (IPTi) reduces early childhood malaria-related morbidity. While genotypic drug resistance markers have proven useful in predicting the efficacy of antimalarial drugs in case management, there are few equivalent data relating to their protective efficacy when used as IPTi. The present data from an IPTi trial in Papua New Guinea demonstrate how these markers can predict protective efficacy of IPTi for both Plasmodium falciparum and Plasmodium vivax.     

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein-related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmosomal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.Netherton syndrome (NS; OMIM 256500) is an autosomal recessive disease regarded as one of the most severe heritable skin disorders affecting newborns. NS involves both cutaneous and immunological abnormalities, including congenital ichthyosiform erythroderma, pronounced peeling of the skin with detachment of the stratum corneum (SC) from the underlying epidermis, severe atopy with elevated serum IgE, and a characteristic hair shaft defect (Comel, 1949; Netherton, 1958; Judge et al., 1994; Hausser and Anton-Lamprecht, 1996). Collectively, these detriments represent a serious challenge to neonate health and promote frequent complications, including hypernatremic dehydration, failure to thrive and recurrent bacterial infections that can be life threatening. Previously, we established that the defective gene in NS is SPINK5 (Chavanas et al., 2000), which encodes the multidomain protease inhibitor, lymphoepithelial Kazal-type inhibitor (LEKTI). To date, the majority of SPINK5 mutations known to cause NS introduce a premature stop codon and result in a lack of detectable LEKTI expression (Hovnanian, 2013).NS has brought into sharp focus the need to preserve the balance between proteolysis and inhibition in the epidermis. Similarly, LEKTI has emerged as a key regulator of epidermal proteolysis. Synthesized as a large (145-kD) polyprotein containing 15 Kazal domains, LEKTI is cleaved by furin to liberate a series of smaller fragments comprising one or more inhibitory units that target distinct protease subsets (Bitoun et al., 2003; Fortugno et al., 2011). LEKTI inhibits several members of the kallikrein-related peptidase (KLK) serine protease family (KLK5, KLK7, and KLK14; Deraison et al., 2007; Fortugno et al., 2011). Additionally, LEKTI has been recently suggested to inhibit caspase-14 (Bennett et al., 2010). Collectively, these proteases are known to hold prominent roles in the SC. KLK5, KLK7, and KLK14 contribute to desquamation by degrading desmosomal cadherins such as desmoglein-1 and desmocollin-1 (Caubet et al., 2004; Fortugno et al., 2011) whereas caspase-14 is needed to complete the processing of filaggrin (Flg; Denecker et al., 2007; Hoste et al., 2011). KLK5 and KLK14 are also able to stimulate proinflammatory and proallergic signals via protease-activated receptor 2 (PAR2; Stefansson et al., 2008; Briot et al., 2009) and KLK5 and KLK7 are linked to the maturation of cathelicidin antimicrobial peptides (Yamasaki et al., 2006). Thus, LEKTI coordinates the timing of several important proteolytic events in epidermal physiology and its absence in NS causes dysregulation of multiple pathways.The development of Spink5-deficient mice provided the first opportunity to unravel the complex pathophysiology of NS in an in vivo experimental model (Yang et al., 2004; Descargues et al., 2005; Hewett et al., 2005; Briot et al., 2009). Spink5^−/− animals display a phenotype highly reminiscent of NS, replicating cutaneous and inflammatory aspects of the disease. Loss of LEKTI causes detachment of the SC from the underlying granular layer (GR) because of unopposed proteolytic activity and premature degradation of desmosomes (Yang et al., 2004; Descargues et al., 2005). Keratinocyte hyperproliferation, abnormal distribution of differentiation markers, accelerated Flg degradation, and lipid defects are also evident (Descargues et al., 2005; Bonnart et al., 2010). Concurrently, uncontrolled proteolytic activity propagates activation of epidermal proinflammatory and proallergic signaling pathways. In particular, proteolytic activation of PAR2 results in elevated expression of the pro-Th2 cytokine, thymic stromal lymphopoietin (TSLP), as well as several other proinflammatory and proallergic mediators (Briot et al., 2009).Despite the neonatal lethality of Spink5-deficient mice (Yang et al., 2004; Descargues et al., 2005; Hewett et al., 2005), considerable progress has been made on detailing the biological pathways involved in NS pathophysiology. However, the significance of each protease implicated in the disease remains unclear. Loss of LEKTI leaves the activity of several proteases unopposed (Descargues et al., 2005; Deraison et al., 2007), many of which are capable of degrading desmosomes or filaggrin, and stimulating inflammation. Protease activation cascades present an additional layer of complexity by providing an avenue for proteases not targeted by LEKTI to be involved in NS, such as matriptase (Sales et al., 2010) and elastase-2 (ELA2; Bonnart et al., 2010). These unknowns conceal the identity of the most promising pharmaceutical targets in NS and represent a major obstacle in developing targeted therapies for NS and related skin disorders. Additionally, there is a current need to develop new animal models to study further aspects of NS pathophysiology, as Spink5^−/− mice uniformly do not survive for more than a few hours after birth because of rapid dehydration (Yang et al., 2004; Descargues et al., 2005; Hewett et al., 2005).In this study, we developed a new transgenic murine model expressing human KLK5 in the GR of the epidermis to assess the role of this protease in NS. KLK5 has been reported to cleave several desmosomal cadherins in vitro (Caubet et al., 2004; Descargues et al., 2006), to activate PAR2 in cultured keratinocytes (Stefansson et al., 2008) and has a prominent role in the proposed KLK proteolytic activation cascade (Brattsand et al., 2005). This study reveals that elevated KLK5 expression, even in the presence of functional Lekti, is sufficient to trigger the majority of the clinical hallmarks of NS. These findings establish the important role of KLK5 in NS pathophysiology and demonstrate its considerable potential as a therapeutic target in this severe genetic skin disorder.     

Mediterranean Diet and Breast Density in the Minnesota Breast Cancer Family Study

Mediterranean populations' lower breast cancer incidence has been attributed to a traditional Mediterranean diet, but few studies have quantified Mediterranean dietary pattern intake in relation to breast cancer. We examined the association of a Mediterranean diet scale (MDS) with mammographic breast density as a surrogate marker for breast cancer risk. Participants completed a dietary questionnaire and provided screening mammograms for breast density assessment using a computer-assisted method. Among 1,286 women, MDS was not clearly associated with percent density in multivariate linear regression analyses. Because of previous work suggesting dietary effects limited to smokers, we conducted stratified analyses and found MDS and percent density to be significantly, inversely associated among current smokers (β = ?1.68, P = 0.002) but not among nonsmokers (β = ?0.08, P = 0.72; P for interaction = 0.008). Our results confirm a previous suggestion that selected dietary patterns may be protective primarily in the presence of procarcinogenic compounds such as those found in tobacco smoke.     

Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

ABSTRACT: BACKGROUND: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus. Results: The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% +/- 98.3%, +22.4% +/- 17.2%, and -15.7% +/- 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. Conclusions: In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose-response relationship.     

Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG)

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non–small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data.Patients and MethodsIn this retrospective, global, multi-center study ({"type":"clinical-trial","attrs":{"text":"NCT04179890","term_id":"NCT04179890"}}NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or “other” mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS).ResultsOverall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years.ConclusionIn a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations.