Sherie A. Dowsett

Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients

EXPEDITION and EXPEDITION2 were identically designed placebo‐controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid‐β peptide, on cognitive and functional decline over 80 weeks in patients with mild‐to‐moderate Alzheimers disease (AD). Primary findings for both studies have been published.

Oral Helicobacter pylori: Can We Stomach It?

Helicobacter pylori infection is one of the most common in man. The bacterium primarily resides in the human stomach, where it plays a significant role in gastric disease. If the spread of H. pylori is to be prevented, an understanding of the transmission process is essential. The oral cavity has been proposed as a reservoir for gastric H. pylori, which has been detected by culture and PCR in both dental plaque and saliva. This review will discuss the evidence for the role of the oral cavity in the transmission of gastric H. pylori. Moreover, the difficulties encountered in addressing this topic, possible directions for future research, and the implications for the dental profession are discussed.

Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes in The Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors

Background— The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc). Methods and Results— Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Womens Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women ≥60 and <70 or ≥70 years of age. Conclusions— In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was similar across the prespecified subgroups.

Safety assessment of raloxifene over eight years in a clinical trial setting.

ABSTRACT Objective: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting. Methods: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista† (CORE) trial. MORE was an international, 4‐year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4‐year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifenes effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fishers exact test. † Evista is a registered trade name of Eli Lilly and Company, Indianapolis, USA Results: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups ( p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively ( p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93–3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups ( p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo ( p = 0.028, p < 0.001, and p = 0.008, respectively). Conclusion: These 8‐year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Drug development in Alzheimer’s disease: the path to 2025

The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.

Effect of Raloxifene on Stroke and Venous Thromboembolism According to Subgroups in Postmenopausal Women at Increased Risk of Coronary Heart Disease

Background and Purpose— Raloxifene, a selective estrogen receptor modulator, reduces risk of invasive breast cancer and osteoporosis, but the effect on risk for stroke and venous thromboembolism in different patient subgroups is not established. The purpose of this analysis was to evaluate the effect of raloxifene on the incidence of all strokes, stroke deaths, and venous thromboembolic events according to participant subgroups. Methods— This was a secondary end point analysis of an international, randomized, placebo-controlled clinical trial of 10 101 postmenopausal women with or at increased risk of coronary heart disease followed a median of 5.6 years. Strokes, venous thromboembolic events, and deaths were adjudicated by expert centralized committees. Strokes were categorized as ischemic, hemorrhagic, or undetermined and venous thromboembolic events were subclassified. Results— The incidences of all strokes did not differ between raloxifene (incidence rate per 100 woman-years=0.95) and placebo (incidence rate=0.86) treatment groups (P=0.30). In women assigned raloxifene versus placebo, there was a higher incidence of fatal strokes (incidence rates=0.22 and 0.15, respectively, P=0.0499) and venous thromboembolic events (incidence rates=0.39 and 0.27, respectively, P=0.02). No significant subgroup interactions were found except that there was a higher incidence of stroke associated with raloxifene use among current smokers. Conclusions— In postmenopausal women at increased risk for coronary events, the incidences of venous thromboembolism and fatal stroke but not all strokes were higher in those assigned raloxifene versus placebo. Raloxifene’s effect did not differ across subgroups, except that the risk of stroke differed by smoking status. Treatment decisions about raloxifene should be based on a balance of projected absolute risks and benefits.

Effect of Raloxifene on the Incidence of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Categorized by Breast Cancer Risk

Purpose: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. Experimental Design: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N = 7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N = 4,011), were analyzed. Prespecified subgroups were defined by age (≥65 versus <65 years), age at menopause (≥49 versus <49 years), body mass index (≥25 versus <25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus <5, >10 versus <5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (≥1.67 versus <1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. Results: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P < 0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P = 0.04). Conclusions: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.

Efficacy and safety of tadalafil once daily : considerations for the practical application of a daily dosing option

ABSTRACT Objective: To provide clinically relevant information on tadalafil 2.5 or 5 mg once daily for the treatment of erectile dysfunction (ED), by reviewing safety and efficacy study findings. Findings from an integrated analysis of trials of tadalafil 10 and 20 mg as needed are presented to provide context for the daily dosing regime. Research design and methods: Of the three studies that included approved once-daily doses, two were conducted in the general ED population and one in a diabetic ED population. An integrated analysis was performed using 12-week efficacy and safety data from the studies conducted in the general ED population. Results: In the general ED population, the 12-week mean International Index of Erectile Function (IIEF) erectile function (EF) domain scores increased by 6.2 to an endpoint score of 19.2 and by 8.6 to 21.9 for 2.5 and 5 mg doses, respectively, versus an increase of 1.3 to 14.9 for placebo (p < 0.01). Mean successful intercourse attempts (SEP3) were 50% and 62% for tadalafil 2.5 and 5 mg once daily, respectively, versus 33% for placebo (p < 0.01). These findings were consistent with those for tadalafil as needed. In 1- and 2-year open label extensions of tadalafil 5 mg once daily, efficacy was maintained. In the diabetic ED population, 12-week mean IIEF EF scores increased by 4.8 to 18.3 and 4.5 to 17.2 with tadalafil 2.5 and 5 mg, respectively, versus an increase of 1.3 to 14.7 for placebo (p < 0.01). Mean successful intercourse attempts were more than 40% for each tadalafil dose, versus 28% for placebo (p < 0.01). The profile of treatment-emergent adverse events with tadalafil once daily was similar to that previously reported with as-needed treatment; the most common adverse events with tadalafil (dyspepsia, nasopharyngitis, headaches) were reported in ≤4% of participants. Conclusions: Findings from the three published studies support a favorable risk–benefit balance for tadalafil 2.5 or 5 mg once daily. Although no direct comparison studies were performed (no head-to-head trials), efficacy and safety findings were consistent with those with tadalafil as needed.

Role of raloxifene in breast cancer prevention in postmenopausal women: clinical evidence and potential mechanisms of action.

BACKGROUND Raloxifene is a selective estrogen-receptor modulator (SERM) indicated for the prevention and treatment of osteoporosis in postmenopausal women. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, an osteoporosis treatment trial, raloxifene therapy was associated with a reduced incidence of invasive, estrogen receptor (ER)-positive breast cancer compared with placebo (relative risk, 0.16; 95% CI, 0.09-0.30). OBJECTIVE This review summarizes available preclinical and clinical data pertaining to a potential role for raloxifene in the prevention of breast cancer, and examines the mechanisms of action by which raloxifene may exert an effect. METHODS Relevant articles were identified through a search of MEDLINE for English-language studies published between 1966 and January 2003. Search terms included raloxifene, keoxifene, tamoxifen, SERM, estrogen, estrogen receptor, breast, mammary, growth factors, and apoptosis. The reference lists of identified articles were reviewed for additional publications. RESULTS Both preclinical and clinical data suggest a role for raloxifene in the prevention of breast cancer. Like tamoxifen, raloxifene acts as an estrogen antagonist in breast tissue through competitive binding to the ER. Raloxifene may also inhibit breast tissue proliferation through mechanisms independent of the ER. CONCLUSIONS Given raloxifenes mechanism of action and the preclinical evidence for its role in breast cancer prevention, a clinically favorable effect seems feasible. Results of ongoing clinical studies will provide evidence to support or refute the clinical findings of MORE and thus raloxifenes role in the breast cancer prevention.

Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings.

Abstract Objective: Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable risk–benefit profile in a Phase 3 study of patients with Alzheimer’s disease (IDENTITY trials), and clinical development was halted. To assist in future development of γ-secretase inhibitors, we report detailed safety findings from the IDENTITY study, with emphasis on those that might be mechanistically linked to γ-secretase inhibition. Research design and methods: The IDENTITY trial was a double-blind, placebo-controlled trial of semagacestat (100 mg and 140 mg), in which 1537 patients age 55 years and older with probable Alzheimer’s disease were randomized. Treatment-emergent adverse events (TEAEs) are reported by body system along with pertinent laboratory, vital sign, and ECG findings. Results: Semagacestat treatment was associated with increased reporting of suspected Notch-related adverse events (gastrointestinal, infection, and skin cancer related). Other relevant safety findings associated with semagacestat treatment included cognitive and functional worsening, skin-related TEAEs, renal and hepatic changes, increased QT interval, and weight loss. With few exceptions, differences between semagacestat and placebo treatment groups were no longer significant after cessation of treatment with active drug. Conclusions: Many of these safety findings can be attributed to γ-secretase inhibition, and may be valuable to researchers developing γ-secretase inhibitors.