Aaron Leigh Schacht

How to improve R&D productivity: the pharmaceutical industry's grand challenge

The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.

Serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologs

Abstract Analogs of D-Phe-Pro-Agmatine were assayed for inhibititory activity versus thrombin, trypsin, plasmin, n-tPA and urokinase. The X-ray structure of the thrombin/D-Phe-Pro-Agmatine co-crystal revealed that the agmatine and analogous arginals have very similar bound conformations.

Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention: A Randomized Clinical Trial

Importance Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. Objective To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. Design, Setting, and Participants A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug. Interventions Short-term migraine treatments were allowed as needed except for opioids or barbiturates. Main Outcomes and Measures To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization. Results Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab. For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability −4.8 days; 90% BCI, −5.4 to −4.2 days vs 95% superiority threshold [Bayesian analysis] −3.7 days; 90% BCI, −4.1 to −3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea. Conclusions and Relevance Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine. Trial Registration clinicaltrials.gov Identifier: NCT02163993

The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element

Modeling of neutral or mildly basic functional groups in the S1 site of thrombin led to the targeting of imidazole as a S1 binding element and correctly predicted the optimal chain length for connecting this group with the S2 and S3 binding elements. Derivatives of 4-(3-aminopropyl)-imidazole can be selective inhibitors of thrombin demonstrating potent anticoagulant activity.

Modeling Resource Requirements for Pharmaceutical R&D

OVERVIEW: The task of bringing novel pharmaceutical products to market quickly at reasonable cost is daunting. While both pharmaceutical sales and R&D expenses are on the rise, the latter is outpacing the former. In order to increase top-line revenues, pharmaceutical firms have been employing a range of strategies to supplement the vitality of their R&D portfolios. While these strategies have the potential to increase revenues, they typically increase the demand for development resources that are already in short supply. Two models—steady-state and dynamic—allow R&D managers to estimate these resource requirements accurately and allocate them intelligently.

Preparation of 2-hydroxybenzamidines from 3-aminobenzisoxazoles

Abstract 2-Hydroxybenzamidines have been prepared from 3-aminobenzisoxazoles by reductive cleavage of the nitrogen–oxygen bond using catalytic hydrogenation, Zn/AcOH or NiCl 2 /NaBH 4 . This ring-opening reaction can be accomplished chemoselectively in the presence of a variety of hydrogenation-sensitive functional groups including an aryl bromide, benzyl carbamate, and olefin.

N-substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors

Abstract We have prepared a series of tripeptide arginine aldehydes in which the P2 proline has been replaced with a variety of N -substituted glycines. The effects of these modifications on thrombin inhibitory potency and serine protease selectivity were evaluated.