Gabriel Vargas

Biomarkers in schizophrenia

Biomarkers Med. (2014) 8(1), 1–3 1 ISSN 1752-0363 10.2217/BMM.13.138

Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple-dose Studies of Erenumab in Healthy Subjects and Patients With Migraine

Monoclonal antibodies (mAbs) targeting calcitonin gene‐related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin‐induced dermal blood flow, with no apparent dose‐dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention.

Personalized healthcare: how to improve outcomes by increasing benefit and decreasing risk through the use of biomarkers

The use of personalized healthcare is beginning to show promise as a means of increasing benefit and decreasing risk for patients, but much work needs to be done in order to fully exploit the advances in medical science that have occurred over the last 30 years. In particular, molecular approaches that aim to characterize patient individuality must be combined with genetic approaches to capture the promise of this potential revolution in the practice of medicine.

Digital technologies as biomarkers, clinical outcomes assessment, and recruitment tools in Alzheimer's disease clinical trials

Digital technology is transforming the development of drugs for Alzheimers disease and was the topic of the Alzheimers Associations Research Roundtable on its May 23–24, 2017 meeting. Research indicates that wearable devices and unobtrusive passive sensors that enable the collection of frequent or continuous, objective, and multidimensional data during daily activities may capture subtle changes in cognition and functional capacity long before the onset of dementia. The potential to exploit these technologies to improve clinical trials as both recruitment and retention tools as well as for potential end points was discussed. The implications for the collection and use of large amounts of data, lessons learned from other related disease areas, ethical concerns raised by these new technologies, and regulatory issues were also covered in the meeting. Finally, the challenges and opportunities of these new technologies for future use were discussed.

Phase 1, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers

Objectives The aim of this study was to assess the effects of concomitant administration of erenumab and sumatriptan on resting blood pressure, pharmacokinetics, safety, and tolerability in healthy subjects. Methods In this phase 1, parallel-group, one-way crossover, double-blind, placebo-controlled study, healthy adult subjects were randomized (1:2) to receive either intravenous placebo and subcutaneous sumatriptan 12 mg (i.e. two 6-mg injections separated by 1 hour) or intravenous erenumab 140 mg and subcutaneous sumatriptan 12 mg. Blood pressure was measured pre-dose and at prespecified times post-dose. The primary endpoint was individual time-weighted averages of mean arterial pressure, measured from 0 hours to 2.5 hours after the first dose of sumatriptan. Pharmacokinetic parameters for sumatriptan were evaluated by calculating geometric mean ratios (erenumab and sumatriptan/placebo and sumatriptan). Adverse events and anti-erenumab antibodies were also evaluated. Results A total of 34 subjects were randomized and included in the analysis. Least squares mean (standard error) time-weighted averages of mean arterial pressure were 87.4 (1.0) mmHg for the placebo and sumatriptan group and 87.4 (1.2) mmHg for the erenumab and sumatriptan group. Mean difference in mean arterial pressure between groups was −0.04 mmHg (90% confidence interval: −2.2, 2.1). Geometric mean ratio estimates for maximum plasma concentration of sumatriptan was 0.95 (90% confidence interval: 0.82, 1.09), area under the plasma concentration–time curve (AUC) from time 0 to 6 hours was 0.98 (90% confidence interval: 0.93, 1.03), and AUC from time 0 to infinity was 1.00 (90% confidence interval: 0.96, 1.05). No clinically relevant safety findings for co-administration of sumatriptan and erenumab were identified. Conclusion Co-administration of erenumab and sumatriptan had no additional effect on resting blood pressure or on pharmacokinetics of sumatriptan. Trial registration: ClinicalTrials.gov, NCT02741310.

Translational Approaches in Alzheimer’s Disease

The identification of potential diagnostic, pharmacodynamic, and patient selection biomarkers has had a profound impact on Alzheimer disease (AD) drug development. These biomarkers include amyloid positron emission tomography imaging and the measurement of amyloid beta in the cerebrospinal fluid. Amyloid-targeting agents can be loosely categorized into three categories: (1) agents that are designed to prevent the aggregation and formation of amyloid plaques, (2) agents that are designed to stimulate the innate immune system to clear existing amyloid plaques and prevent further deposition, and (3) agents that prevent the formation of the precursor of amyloid, the Aβ peptide. Biomarkers have been instrumental in determining the disease-modifying effects of these treatments and thus ultimately have an impact on whether drugs continue in development all the way to approval or are instead terminated. Furthermore, the use of newly developed biomarkers has had a profound impact on the diagnosis of this disorder. This chapter reviews the role of amyloid in AD and shows examples of translational biomarker strategies used in drug development for antiamyloid therapeutic agents.