Toward a Functional Definition of a “Rare Disease” for Regulatory Authorities and Funding Agencies

AbstractBackgroundThe designation of a disease as “rare” is associated with some substantial benefits for companies involved in new drug development, including expedited review by regulatory authorities and relaxed criteria for reimbursement. How “rare disease” is defined therefore has major financial implications, both for pharmaceutical companies and for insurers or public drug reimbursement programs. All existing definitions are based, somewhat arbitrarily, on disease incidence or prevalence.ObjectivesWhat is proposed here is a functional definition of rare based on an assessment of the feasibility of measuring the efficacy of a new treatment in conventional randomized controlled trials, to inform regulatory authorities and funding agencies charged with assessing new therapies being considered for public funding.MethodsIt involves a five-step process, involving significant negotiations between patient advocacy groups, pharmaceutical companies, physicians, and public drug reimbursement programs, designed to establish the feasibility of carrying out a randomized controlled trial with sufficient statistical power to show a clinically significant treatment effect.Results and ConclusionsThe steps are as follows: 1) identification of a specific disease, including appropriate genetic definition; 2) identification of clinically relevant outcomes to evaluate efficacy; 3) establishment of the inherent variability of measurements of clinically relevant outcomes; 4) calculation of the sample size required to assess the efficacy of a new treatment with acceptable statistical power; and 5) estimation of the difficulty of recruiting an adequate sample size given the estimated prevalence or incidence of the disorder in the population and the inclusion criteria to be used

Immune checkpoint inhibitors: new strategies to checkmate cancer

Immune checkpoint inhibitors (ICIs) targeting Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) or Programmed cell Death protein 1 (PD-1) receptors have demonstrated remarkable efficacy in subsets of patients with malignant disease. This emerging treatment modality holds great promise for future cancer treatment and has engaged pharmaceutical research interests in tumour immunology. While ICIs can induce rapid and durable responses in some patients, identifying predictive factors for effective clinical responses has proven challenging. This review summarises the mechanisms of action of ICIs and outlines important pre-clinical work that contributed to their development. We explore clinical data that has led to disease-specific drug licensing, and highlight key clinical trials that have revealed ICI efficacy across a range of malignancies. We describe how ICIs have been used as part of combination therapies, and explore their future prospects in this area. We conclude by discussing the incorporation of these new immunotherapeutics into precision approaches to cancer therapy

Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Purpose: Sorafenib is the current standard therapy for advanced HCC, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in HCC patients from the phase 3 SEARCH trial. Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or to HCC were measured in baseline plasma samples. Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n=243; sorafenib plus placebo, n=251). Treatment arm–independent analyses showed that elevated HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj] P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly associated with poor OS in multivariate analyses, and low plasma KIT (HR, 0.75 [high vs low]; P=0.0233; e-adj P=0.2793) tended to correlate with poorer OS. High plasma VEGF-C independently correlated with longer TTP (HR, 0.633; e-adj P=0.0010) and trended toward associating with improved disease control rate (univariate:OR, 2.047; P=0.030; e-adj P=0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGF-A, KIT, epigen, and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150; P<0.00001). No biomarker predicted efficacy from erlotinib. Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers plus epigen constituted a multimarker signature for improved OS

Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine

Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment-refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway

The continuing saga of Sakurai's object (V4334 Sgr): dust production and helium line emission

We report further UKIRT spectroscopic observations of Sakurai's object (V4334 Sgr) made in 1999 April/May in the 1-4.75 µm range, and find that the emission is dominated by amorphous carbon at T[subscript d] ~ 600. The estimated maximum grain size is 0.6 µm, and the mass lower limit is 1.7 ± 0.2 x 10[superscript -8] M[subscript ¤] to 8.9 ± 0.6 x 10[superscript -7] M[subscript ¤] for distances of 1.1-8 kpc. For 3.8 kpc the mass is 2.0 ± 0.1 x 10[superscript -7] M[subscript ¤]. We also report strong He i emission at 1.083 µm, in contrast to the strong absorption in this line in 1998. We conclude that the excitation is collisional, and is probably caused by a wind, consistent with the P Cygni profile observed by Eyres et al. in 1998

Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion

Decreased forkhead box O1 (FoxO1) activity induces hyperlipidemia and increased PPARγ, leading to hyperlipidemia in association with endoplasmic reticulum (ER) stress. In the liver, aging and comorbidities such as hyperlipidemia and diabetes significantly influence a wide variety of steatosis, but the underlying mechanisms are complex and remain elusive.To establish the modulatory role of FoxO1 and the functional consequences of its altered interaction with PPARγ in the present study, we utilized a cell culture system, aged rats and diabetic db/db mice.We found that, under ER stress, FoxO1 induces PPARγ-mediated lipid accumulation in aged rat livers. Our data showed that the FoxO1-induced hepatic lipid accumulation was negatively regulated by Akt signaling. PPARγ, a key lipogenesis transcription factor, was increased in aged liver, resulting in lipid accumulation via hepatic ER stress under hyperglycemic conditions. We further demonstrated that loss of FoxO1 causes a decline in PPARγ expression and reduces lipid accumulation. In addition, the interaction between FoxO1 and PPARγ was shown to induce hepatic steatosis in aging and db/db mice.We provide evidence that, in aged rats, FoxO1 interaction with PPARγ promotes hepatic steatosis, due to hyperglycemia-induced ER stress, which causes an impairment in Akt signaling, such in aging-related diabetes.Environmental Biolog

Lepidoptera Pest Species Response to Mid-Summer Fire

In the American Midwest, summer fires are infrequent, and there is little information on their impact on ecosystems. After an accidental wildfire in a 20 ha grassland restoration, new growth provided effective substrate for the noctuid species corn earworm, Helicoverpa zea (Boddie), and tobacco budworm, Heliothis virescens (Fabricius). These agricultural pests feed on a number of important crop species and have been implicated in crop losses of up to 50%. Invertebrate collections were made at 16 days, 45 days, 70 days, and 101 days post fire. A comparison of burned and unburned areas at 70 days post fire show 18 times the number of Lepidoptera larvae collected in pitfall traps in the burned area compared to the adjacent unburned area of the grasslands. These findings demonstrate that a mid-summer fire can affect the abundance of economically important insects.Environmental Biolog

Ovarian structures and uterine environment are associated with phenotypic and genetic merit for performance in lactating dairy cows

peer-reviewedThe objective of this study was to estimate the association between detailed reproductive phenotypes for cows categorized as divergent for phenotypic and genetic performance. The hypothesis was that higher yielding animals, either phenotypically or genetically, would have compromised ovarian and uterine reproductive performance. Detailed reproductive traits including multiple ovulations, cystic ovarian structures, corpus luteum (CL) presence, and uterine environment were available on 9675 ultrasound records from 8174 dairy lactating cows, calved between 10 and 70 days. Cows were categorized, within parity, into low, average, or high for each of the performance traits. There was a greater likelihood of multiple ovulations in cows with greater phenotypic yields (odds ratio: 1.53–1.81) and greater genetic merit for yield (odds ratio: 1.31–1.59) relative to lower performing contemporaries. After adjustment for genetic merit, a similar trend of increased odds (odds ratio: 1.29–1.87) of multiple ovulations in higher yielding cows was observed compared with the lowest yielding category. There was no association between either phenotypic milk composition or genetic merit for milk composition with the likelihood of multiple ovulations. The likelihood of cystic ovarian structures was highest in cows with greatest phenotypic milk yields (odds ratio: 2.75–3.24), greater genetic merit for milk yield (odds ratio: 1.30–1.51), and even after adjustment for genetic merit there was a greater likelihood of cystic ovarian structures in cows with the highest milk yields (odds ratio: 2.71–2.95), compared with cows in the lowest category for each of the milk traits. Cows with average phenotypic milk yields were more likely to have a CL, compared with the lowest yielding category (odds ratio: 1.20–1.23), and these associations remained after adjustment for genetic merit of the trait. The likelihood of CL presence was highest in cows with the lowest genetic merit for milk. Lower fat:protein ratio was associated with an increased likelihood of CL presence compared with cows with greater fat:protein ratio and cows with the highest phenotypic milk composition were more likely to have a CL compared with cows in the lowest composition category. Genetic predisposition to higher somatic cell score was associated with a reduced risk of multiple ovulations (odds ratio: 0.69; 95% CI: 0.55–0.87) but an increased likelihood of CL presence (odds ratio: 2.66; 95% CI: 2.09–3.37) and poorer uterine health score (odds ratio: 1.36; 95% CI: 1.20–1.55). There was a lower likelihood of multiple ovulations, cystic ovarian structures, and poorer uterine health and an increased likelihood of CL presence in cows with superior genetic merit for reproductive performance and survival

Adult firefly abundance is linked to weather during the larval stage in the previous year

Environmental Biolog