Repackaging FDA-approved drugs for degenerative diseases: promises and challenges

Repurposing refers to the therapeutic use of a drug or drug candidate for a disease other than that for which it was originally intended. Repurposing is attractive as a drug development strategy since much is known about approved agents including their drug-likeness and pharmacokinetic features, dosing, safety, tolerability, formulation and manufacturing. Time savings are also robust accounting for several years of the drug development cycle. Tissue and cell-based assays, epidemiologic information and human studies identify approved drugs that might be repurposed from use in Alzheimer's disease and other neurodegenerative disorders. The total number of compounds available for repurposing that are brain-penetrant is relatively small. Intellectual property and patent protection issues for repurposed drugs are hurdles for this approach to drug development. Repurposing may contribute importantly to development of new therapies for neurodegenerative disorders.     

An FDA oncology analysis of antibody-drug conjugates

Antibody-drug conjugates (ADCs) are complex molecules composed of monoclonal antibodies conjugated to potent cytotoxic agents through chemical linkers. Because of this complexity, sponsors have used different approaches for the design of nonclinical studies to support the safety evaluation of ADCs and first-in-human (FIH) dose selection. We analyzed this data with the goal of describing the relationship between nonclinical study results and Phase 1 study outcomes. We summarized the following data from investigational new drug applications (INDs) for ADCs: plasma stability, animal study designs and toxicities, and algorithms used for FIH dose selection. Our review found that selecting a FIH dose that is 1/6th the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys or 1/10th the STD₁₀ in rodents scaled according to body surface area (BSA) generally resulted in the acceptable balance of safety and efficient dose-escalation in a Phase 1 trial. Other approaches may also be acceptable, e.g. 1/10th the HNSTD in monkeys using BSA or 1/10th the NOAEL in monkeys or rodents using body weight for scaling. While the animal data for the vc-MMAE platform yielded variable range of HNSTDs in cynomolgus monkeys, MTDs were in a narrow range in patients, suggesting that for ADCs sharing the same small molecule drug, linker and drug:antibody ratio, prior clinical data can inform the design of a Phase 1 clinical trial.     

Discontinued drugs in 2007: oncology drugs

This perspective is part of an annual series of papers discussing drugs dropped from clinical development in the previous year. Specifically, this paper focuses on the 28 oncology drugs discontinued in 2007. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I – III clinical trials.     

Discontinued drugs in 2008: oncology drugs

The failure of drug candidates in clinical development remains a critical issue for the pharmaceutical and biotechnology industries. This article documents those oncology drugs discontinued in 2008 and briefly reviews reasons for termination of development. Source information was derived from a search of the Pharmaprojects database for drugs reaching phase I – III clinical trials.     

Discontinued drugs in 2010: oncology drugs

The Pharmaceutical Industry is currently undergoing a period of rapid change as the pressures of the financial markets highlight fundamental inefficiencies in the current business model. The Achilles heel for the industry is the unacceptable level of attrition in clinical drug development. An imperative for the industry is to reduce the cost and increase the efficiency of Research and Development (R&D). This article provides an analysis of cancer drugs dropped from the industry pipeline in 2010 and offers a perspective on how the future oncology drug pipeline might evolve.     

Discontinued drugs in 2011: oncology drugs

This year's analysis of discontinued drugs in oncology reveals that the trend of increasing numbers of candidate drug development terminations seen in recent years has continued into 2011. Thirty-seven drugs were dropped from the global oncology development pipeline in 2011, significantly more than the 28 discontinuations reported in 2010. Of note were the number of terminations reported for strategic reasons and the striking number of drugs (23) discontinued in or at the end of Phase I development. This article provides a summary of those drugs discontinued in 2011 and discusses the observations in the context of the rapid changes occurring in the way new anticancer drugs are developed.     

Discontinued drugs in 2010: oncology drugs

The Pharmaceutical Industry is currently undergoing a period of rapid change as the pressures of the financial markets highlight fundamental inefficiencies in the current business model. The Achilles heel for the industry is the unacceptable level of attrition in clinical drug development. An imperative for the industry is to reduce the cost and increase the efficiency of Research and Development (R&D). This article provides an analysis of cancer drugs dropped from the industry pipeline in 2010 and offers a perspective on how the future oncology drug pipeline might evolve.     

Discontinued drugs in 2006: oncology drugs

This perspective is the last in a series of papers discussing drugs dropped from clinical development in 2006. Specifically, this paper focuses on the 16 drugs discontinued for the treatment of cancer, the largest area of pharma R&D. This was based on a search of the Pharmaprojects database for drugs reaching Phase I-III clinical trials.