FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies.

The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration's regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.

Testosterone Therapy for the Treatment of Age-Related Hypogonadism: Risks with Uncertain Benefits.

Testosterone replacement therapy has been approved in the United States since the 1950s for men with "classical" hypogonadism. These men have specific and well-recognized hypothalamic, pituitary, or testicular conditions leading to deficient or absent endogenous testosterone. A more controversial treatment population is aging men, many with comorbidities, who have low serum testosterone concentrations compared with young healthy men and who do not have the well-recognized medical conditions that cause "classical" hypogonadism. Testosterone continues to be widely used in these men with "age-related hypogonadism" even though the benefits of testosterone for this use are uncertain and there are important risks, including a potential risk of major adverse cardiac events for the testosterone class, and two testosterone products with increases in blood pressure that can increase the risk of myocardial infarction and stroke. Given the uncertain clinical benefit of testosterone in men with "age-related hypogonadism" in the face of known and potential adverse outcomes, none of the testosterone products is FDA approved for such use.

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

A protocol for active surveillance of acute myocardial infarction in association with the use of a new antidiabetic pharmaceutical agent.

PURPOSE: To describe a protocol for active surveillance of acute myocardial infarction (AMI) in users of a recently approved oral antidiabetic medication, saxagliptin, and to provide the rationale for decisions made in drafting the protocol. METHODS: A new-user cohort design is planned for evaluating data from at least four Mini-Sentinel data partners from 1 August 2009 (following US Food and Drug Administration's approval of saxagliptin) through mid-2013. New users of saxagliptin will be compared in separate analyses with new users of sitagliptin, pioglitazone, long-acting insulins, and second-generation sulfonylureas. Two approaches to controlling for confounding will be evaluated: matching by exposure propensity score and stratification by AMI risk score. The primary analyses will use Cox regression models specified in a way that does not require pooling of patient-level data from the data partners. The Cox models are fit to summarized data on risk sets composed of saxagliptin users and similar comparator users at the time of an AMI. Secondary analyses will use alternative methods including Poisson regression and will explore whether further adjustment for covariates available only at some data partners (e.g., blood pressure) modifies results. RESULTS: The results of this study are pending. CONCLUSIONS: The proposed protocol describes a design for surveillance to evaluate the safety of a newly marketed agent as postmarket experience accrues. It uses data from multiple partner organizations without requiring sharing of patient-level data and compares alternative approaches to controlling for confounding. It is hoped that this initial active surveillance project of the Mini-Sentinel will provide insights that inform future population-based surveillance of medical product safety.

Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus.

All medications currently approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus are indicated to improve glycemic control. Since 1995, FDA has used HbA1c as the primary basis for approval of these therapies because a reduction in blood glucose lessens the symptoms of hyperglycemia and lowering of HbA1c has been shown to reduce the risk for some of the chronic complications of diabetes. Despite evidence of clinical benefit with therapies that reduce HbA1c, concerns have been raised that some diabetes medications may increase cardiovascular risk in a patient population that is already vulnerable to cardiovascular disease. Therefore, FDA convened a public advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for medications developed for the treatment of type 2 diabetes. After considering the advisory panel's recommendations and other data, FDA published a guidance document requesting evidence showing that new treatments for type 2 diabetes do not result in an unacceptable increase in cardiovascular risk. This review article begins by summarizing the events leading up to publication of this guidance. Subsequent sections discuss the guidance itself as well as general considerations for implementing the new cardiovascular recommendations. The new approach to developing medications for the treatment of type 2 diabetes will lead to evaluation in patients more representative of those who will use these therapies, if approved, and will help healthcare providers make informed decisions when choosing a medication within the growing treatment armamentarium for type 2 diabetes.

Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVES: To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We simultaneously measured the serum concentrations of 12 steroids in patients with CP/CPPS and controls, using isotope dilution liquid chromatography, followed by atmospheric pressure photospray ionization and tandem mass spectrometry. RESULTS: We evaluated 27 patients with CP/CPPS and 29 age-matched asymptomatic healthy controls. In the mineralocorticoid pathway, progesterone was significantly greater, and the corticosterone and aldosterone concentrations were significantly lower, in the patients with CP/CPPS than in the controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower and the cortisol concentrations were not different between the patients and controls. In the sex steroid pathway, the androstenedione and testosterone concentrations were significantly greater in those with CP/CPPS than in the controls. The estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different between the patients and controls. The National Institutes of Health-Chronic Prostatitis Symptom Index total and pain domain scores correlated positively with the 17-hydroxyprogesterone and aldosterone (P <0.001) and negatively with the cortisol (P <0.001) concentrations. CONCLUSIONS: Our results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biologic basis of CP/CPPS. Follow-up studies should explore the possibility that patients with CP/CPPS meet the diagnostic criteria for nonclassic congenital adrenal hyperplasia and whether the hormonal findings improve or worsen in parallel with symptom severity.

Beneficial effects of eplerenone versus hydrochlorothiazide on coronary circulatory function in patients with diabetes mellitus.

CONTEXT: Impaired coronary circulatory function predicts cardiovascular events, the leading cause of death in patients with diabetes mellitus. Aldosterone causes cardiovascular injury and is not suppressed by chronic angiotensin converting enzyme (ACE) inhibitor therapy. OBJECTIVE: Our objective was to assess whether mineralocorticoid receptor activation contributes to coronary circulatory dysfunction in patients with diabetes who are already receiving ACE inhibitor therapy. DESIGN AND SETTING: A randomized, double-blind, crossover study with an intervening washout period of at least 4 wk was conducted with ambulatory patients from the community. PATIENTS: Patients included 16 subjects (11 men, eight Caucasians; mean age, 53 yr; mean body mass index, 38.0 kg/m2) with diabetes and albuminuria but without clinical cardiovascular disease. INTERVENTIONS: ACE inhibitors were switched to enalapril 20 mg daily, and other antihypertensives were discontinued. Amlodipine 5-10 mg daily was added to achieve blood pressures less than 130/80 mm Hg. Subjects then received, in random order, 6 wk of the mineralocorticoid receptor antagonist eplerenone 50 mg (with placebo pill) daily and 6 wk of another diuretic, hydrochlorothiazide 12.5 mg (with potassium 10 mEq) daily. MAIN OUTCOME MEASURES: Before and after each 6-wk treatment period, we measured coronary circulatory function (adenosine-stimulated myocardial perfusion reserve) and endothelial function (brachial artery reactivity and peripheral arterial tonometry). RESULTS: The eplerenone and hydrochlorothiazide groups had similar blood pressures, serum potassium, glycemia, and endothelial function. Although pretreatment myocardial perfusion reserve did not differ between groups, myocardial perfusion reserve was significantly higher after eplerenone than after hydrochlorothiazide (median 1.57 vs. 1.30; P = 0.03). CONCLUSIONS: Mineralocorticoid receptor blockade improves coronary circulatory function compared with hydrochlorothiazide in patients with diabetes already receiving ACE inhibitor therapy.

FDA's proactive role in the development of an artificial pancreas for the treatment of diabetes mellitus.

One of the critical path initiatives of the Food and Drug Administration (FDA) is to accelerate the development and availability of a safe and effective artificial pancreas for the treatment of diabetes mellitus. The FDA has established a multidisciplinary group of scientists and clinicians, in partnership with the National Institutes of Health (NIH), to address the clinical, scientific and regulatory challenges related to this unique medical product.:

Sex hormone-binding globulin and serum testosterone are inversely associated with C-reactive protein levels in postmenopausal women at high risk for cardiovascular disease.

PURPOSE: C-reactive protein (CRP), androgens, and menopausal loss of endogenous estrogens are associated with cardiovascular disease (CVD). We hypothesized that high androgens, low estradiol, and low sex hormone-binding globulin (SHBG) would be associated with high CRP in postmenopausal women. METHODS: CRP, SHBG, estradiol, and total testosterone were measured using baseline bloods of 221 hormone therapy (HT)-nonusers and 162 HT-users from a cross-sectional analysis in a nested case-control sample of the Women's Health Study. Hormones and CRP were ln-transformed and relationships were assessed with Spearman correlations and linear regression. RESULTS: ln-SHBG (beta=-0.40; p<0.01) and ln-testosterone (beta=-0.24; p=0.04) were the only independent hormonal predictors of ln-CRP among HT-nonusers after adjusting for age, hypertension, smoking, body mass index, diabetes, exercise, HDL cholesterol, alcohol intake, and CVD occurrence during follow-up. Upon stratification, the association between ln-SHBG and ln-CRP persisted among HT nonusers who subsequently developed CVD (beta=-0.55; p=0.01), but not among women who remained CVD-free (p=0.28). The inverse relationship between ln-SHBG and ln-CRP was strongest among the leanest women. None of the sex-hormones predicted ln-CRP among HT-users. CONCLUSIONS: SHBG and total testosterone were inversely associated with CRP among HT nonusers in this study. The relationship between SHBG and CRP was more strongly inverse among leaner women.

Few predictors of massive deep vein thrombosis.

Factors that predispose to thrombus propagation from the femoropopliteal veins to the pelvic veins are poorly understood. Our goal was to determine whether there are characteristics that identify patients with massive deep vein thrombosis (DVT). We compared the 122 (2.5%) patients presenting with massive DVT (pelvic plus lower-extremity DVT) to the 4,674 (97.5%) patients with isolated lower-extremity DVT from a prospective United States multicenter DVT registry. Patients with massive DVT were younger (59.4+/-18.9 years vs. 64.3+/-16.8 years; p<0.01), less likely to have hypertension (40% vs. 51%; p=0.02), and more likely to smoke (21% vs. 13%; p=0.02) and have ongoing radiation therapy (7% vs. 3%; p=0.02). The massive DVT group more commonly presented with extremity edema (80% vs. 69%; p<0.01) and erythema (21% vs. 12%; p<0.01) than the isolated lower-extremity DVT group. However, after multivariable logistic regression analysis, extremity erythema (adjusted odds ratio 1.86; 95% CI 1.13-3.04) was the only independent sequela of massive DVT and younger age (adjusted odds ratio 1.17 per decreasing decade of age; 95% confidence interval: 1.02-1.34) was the only independent predictor of massive DVT. Thrombus propagation from the femoropopliteal system cannot be reliably predicted using demographic or clinical characteristics.