Central Nervous System Drug Development Research Articles

Central Nervous System Drug Development, Basic, and Clinical Research

From the *New York University School of Medicine, New York, NY; †Stanford University School of Medicine, Stanford, CA; and ‡Tufts University School of Medicine, Boston, MA. Reprints: Ira D. Glick, MD, Stanford University School of Medicine, 401 Quarry Rd, Stanford, CA 94305 (e-mail: [email protected]).

CNS Drug Development

This column, the third in a series on central nervous system (CNS) drug development, discusses advances during the first decade of the 21st century and directions the field may take in the next 10 years. By identifying many possible new drug targets, the human genome project has created the potential to develop novel central nervous system (CNS) drugs with new mechanisms of action. At the same time, this proliferation of possible new targets has complicated the drug development process, since research has not yet provided guidance as to which targets may be most fruitful. This and other factors (eg, increasing regulatory requirements) have increased the cost and complexity of the drug development process. In addition, as more is learned about the biology of psychiatric illnesses, syndromes may be subdivided into more specific entities that are better understood from a pathophysiological and pathoetiological perspective. This is likely to lead to development of more targeted treatments focused on underlying causes of illness as well as prevention. The development of drugs for Alzheimer's disease is discussed as a possible model for future CNS drug development. We are at the beginning of an era when it is likely that the way in which CNS drugs are developed will need to be rethought, which will call for flexibility and creativity on the part of both drug developers and clinical researchers.

Tutorial on Drug Development for Central Nervous System

Many neurodegenerative diseases, such as Alzheimer`s and Parkinson`s disease, are devastating disorders that affect millions of people worldwide. However, the number of therapeutic options remains severely limited with only symptomatic management therapies available. With the better understanding of the pathogenesis of neurodegenerative diseases, discovery efforts for disease-modifying drugs have increased dramatically in recent years. However, the process of translating basic science discovery into novel therapies is still lagging behind for various reasons. The task of finding new effective drugs targeting central nervous system (CNS) has unique challenges due to blood-brain barrier (BBB). Furthermore, the relatively slow progress of neurodegenerative disorders create another level of difficulty, as clinical trials must be carried out for an extended period of time. This review is intended to provide molecular and cell biologists with working knowledge and resources on CNS drug discovery and development.

CNS Drug Development

This column is the second in a series on central nervous system (CNS) drug development. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 2) reviews the history of CNS drug development from the 1960s to the 1990s. During the 1960s, researchers acquired a much clearer understanding of basic CNS pharmacology (e.g., biogenic amine transmitter systems in the brain) and developed the first animal models of psychiatric illness that could be used to test potential psychiatric medications. During the 1970s, drug development scientists used their expanded understanding of receptor binding affinity and the theories and techniques developed in the 1950s and 1960s to produce new CNS-active medications. They did this by adding or reducing affinities for certain regulatory proteins (e.g., receptors) to increase positive effects and/or minimize adverse effects. The development of newer antipsychotics and antidepressants is discussed to illustrate this process. The next column in this series will review CNS drug development during the first decade of the 21st century and discuss what directions we can expect the field to take in the next 10 to 20 years.

CNS Drug Development: Part I: The Early Period of CNS Drugs

This column begins a new series on central nervous system (CNS) drug development. This series will review developments up to the present day and end with a forward-looking perspective on what to expect over the next 10-20 years. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 1) reviews the history of CNS drug development from the period before written history through the golden era (i.e., late 1940s-early 1960s) in which the first modern medications for anxiety, bipolar, depressive, and psychotic disorders were discovered by chance. It also describes the early era of rational drug development in which other agents (e.g., thioridazine, fluphenazine, haloperidol, imipramine) were developed based on those first agents. The blueprint laid down for development of antibiotics is reviewed in relation to its impact on CNS drug development. The impact of the blockbuster business model and modern marketing/sales approaches on CNS drug development is also discussed.

Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood-brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic.

CNS Drug Delivery Systems: Novel Approaches

The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available.

Evaluation of the automatic three-dimensional delineation of caudate and putamen for PET receptor occupancy studies

PET receptor occupancy studies with a baseline study and an intervention study are increasingly used as an aid in dose-finding procedures for central nervous system drug development. The aim of this study was to evaluate, and confirm the feasibility of two automatic, paired, three-dimensional delineation methods of striatal structures (caudate and putamen) for the purposes of PET receptor occupancy studies. The automatic extraction was done with the deformable surface models from PET binding potential images. The segmentation result of the baseline study was utilized for segmenting the intervention study. The methods were evaluated with Monte Carlo simulated phantom images, a test-retest dataset with 11C-raclopride, and two receptor occupancy datasets (11C-raclopride and 18F-SPA-RQ). With the test-retest dataset, the reproducibility (normalized absolute differences (NAD)) and reliability (intraclass correlation coefficient (ICC)) of binding potential values were assessed with the proposed methods designed specifically for receptor occupancy and compared with the manual segmentation. A similar comparison was also performed for the receptor occupancy estimates. In the test-retest dataset, the two automatic three-dimensional segmentation methods had mean NADs ranging from 2.44 to 5.11% and ICCs from 0.88 to 0.98. The corresponding values for the manual two-dimensional segmentation were 3.45 to 6.65% and 0.82 to 0.96 (NAD differences non-significant). The automatic methods also yielded similar receptor occupancy values to the manual segmentation method in a range of high and low occupancy values. We believe that the automated three-dimensional segmentation will be useful in enhancing the analysis of large-scale PET receptor occupancy studies with high-resolution scanners.

Implication of Possible Therapies Targeted for the Tachykinergic System with the Biology of Neurokinin Receptors and Emerging Related Proteins

The neurokinin (NK) receptor family has been proposed as targets for neural-related diseases. The experimental studies indicate that this family of receptors might also be targets for malignancies, both solid and hematological tumors. However, an understanding of the biology of other rmolecules with sequence similarity to NK receptors is required. Of significance is the HGFIN gene that shares structural homology with NK1. Through this homology, the HGFIN interacts with the high affinity ligand of NK1, substance P. This report discusses potential applications for targets against NK receptors, and the role of HGFIN in drug designs. This review is relevant for central and peripheral nervous system drug development, and also cancer drugs for breast and neuroblastoma. The potential for leukemia drugs and Patents are also discussed.

A role for fMRI in optimizing CNS drug development

Drug development today needs to balance agility, speed and risk in defining the probability of success for molecules, mechanisms and therapeutic concepts. New techniques in functional magnetic resonance imaging (fMRI) promise to be part of a sequence that could transform drug development for disorders of the central nervous system (CNS) by examining brain systems and their functional activation dynamically. The brain is complex and multiple transmitters and intersecting brain circuits are implicated in many CNS disorders. CNS therapeutics are designed against specific CNS targets, many of which are unprecedented. The challenge is to reveal the functional consequences of these interactions to assess therapeutic potential. fMRI can help optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving success rates and reducing risk, development times and costs of drug development.

P.3.d.006 Pharmacological profile of RGH-188, a novel dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic

The discovery and development of central nervous system (CNS) drugs is an extremely challenging process requiring large resources, timelines, and associated costs. The high risk of failure leads to high levels of risk. Over the past couple of decades PET imaging has become a central component of the CNS drug-development process, enabling decision-making in phase I studies, where early discharge of risk provides increased confidence to progress a candidate to more costly later phase testing at the right dose level or alternatively to kill a compound through failure to meet key criteria. The so called “3 pillars” of drug survival, namely; tissue exposure, target engagement, and pharmacologic activity, are particularly well suited for evaluation by PET imaging. This review introduces the process of CNS drug development before considering how PET imaging of the “3 pillars” has advanced to provide valuable tools for decision-making on the critical path of CNS drug development. Finally, we review the advances in PET science of biomarker development and analysis that enable sophisticated drug-development studies in man.

Experimental medicine in psychiatry

The recent allocation of £15 million by the MRC (Medical Research Council) specifically to support research in experimental medicine (defined as the ‘Investigation undertaken in human beings to identify mechanisms of pathophysiology or disease, or to test the validity and importance of new discoveries or treatments, relating where appropriate to model systems’) underlines the priority currently given to this area of research. The recent interest in experimental, sometimes called ‘translational’ medicine suggests that it is something new. However, the BAP (British Association Psychopharmacology) was established in 1974 to support experimental and translational medicine in the area of psychopharmacology by bringing together the preclinical and clinical arms of this research area. Through its meetings and journal the BAP has been at the forefront of translational medicine in its purest form – combining the knowledge gathered from preclinical and clinical science to provide synergy in the search for new treatments for some of the most devastating disorders known to man. Indeed it is difficult to name a society that does more to put the ‘translational’ into ‘translational medicine’ than the BAP and we have little doubt that psychopharmacology alone could generate world class research proposals that would account for all of the MRC allocation. Another strong supporter of translational medicine is the pharmaceutical industry. Its driving force has been the large markets in psychiatry for medicines such as Risperidone (>$2 billion annual sales) for the treatment of schizophrenia or Duloxetine (>$1 billion annual sales) for depression. Consequently pharmaceutical companies have poured significant resources into discovering and developing new treatments for psychiatric disorders. On the preclinical side of the translational medicine equation, the combined resources of academia and industry have resulted in a phenomenal increase in fundamental knowledge, new experimental techniques and, indeed, whole new classes of candidate compounds. However, clinical translation of these findings directly to benefit psychiatric patients has so far been very limited and most of the medicines we think of as new – the atypical antipsychotics or the SSRIs (Selective Serotonin Reuptake Inhibitors), for example – were conceived as refinements of classical treatments. The failure, so far, of genuine innovation has been disappointing, and so merits closer examination. For example, preclinical and early clinical studies suggested that NK-1 antagonists would be effective antidepressants. The first clinical study was also positive, but subsequent large Phase III studies were not. Uncertainty about the clinical efficacy of the compounds led to the termination of investment by the leading player. Unfortunately, placebo controlled trials in depression are difficult to conduct in patients with significant severity of depression, and placebo response rates are high so confounding detection of positive treatment effects. Such trials are also extremely expensive. Very promising candidate medicines may founder because of chance effects in very expensive clinical studies. There is an evident gap between the preclinical portfolio and such large scale clinical trials. The question is whether we can harness and exploit the strong clinical science base in the UK to fill this gap by generating translational data for new compounds, which would be highly predictive of subsequent clinical utility. There should be no doubt about the unmet needs of the patients. Economically, more beds are occupied by patients with psychiatric disorders than any other patient group; schizophrenia alone costs the National Health Service in England and Wales about £2.9 billion each year. Add in the cost of lost working hours and benefit payments (about 95% of patients with schizophrenia are unemployed) the overall costs rocket. Thus, it would be foolish to doubt the potential benefits of investing in CNS (Central Nervous System) research and development. The existing global market for CNS drugs for 12 months to March 2004 was $59.6 billion and with a 14% increase on the 12 months to March 2003 was the second fastest growing therapeutic category. Unfortunately, the costs of drug development (including lost opportunity costs) continue to spiral and the average cost of development of a new drug is estimated to be about $900 million. Furthermore, the chance of success of a novel compound in Phase 1 reaching the market is 11% for all therapeutic categories and only 8% for CNS disorders. This makes the costs of CNS drug development particularly high and raises the question of why it is more difficult to discover and develop drugs for CNS disorders and why the success rate is not improving (Kola and Landis, 2004). In the past 10 years there has been little improvement in the overall rate of novel compounds in development but there have been significant changes in the causes of attrition. In 1991, the

Central Nervous System Drug Development: An Integrative Biomarker Approach toward Individualized Medicine

Drug development for CNS disorders faces the same formidable hurdles as other therapeutic areas: escalating development costs; novel drug targets with unproven therapeutic potential; and health care systems and regulatory agencies demanding more compelling demonstrations of the value of new drug products. Extensive clinical testing remains the core of registration of new compounds; however, traditional clinical trial methods are falling short in overcoming these development hurdles. The most common CNS disorders targeted for drug treatment are chronic, slowly vitiating processes manifested by highly subjective and context dependent signs and symptoms. With the exception of a few rare familial degenerative disorders, they have ill-defined or undefined pathophysiology. Samples selected for treatment trials using clinical criteria are inevitably heterogeneous, and dependence on traditional endpoints results in early proof-of-concept trials being long and large, with very poor signal to noise. It is no wonder that pharmaceutical and biotechnology companies are looking to biomarkers as an integral part of decision-making process supported by new technologies such as genetics, genomics, proteomics, and imaging as a mean of rationalizing CNS drug development. The present review represent an effort to illustrate the integration of such technologies in drug development supporting the path of individualized medicine.

LC/MS/MS in Drug Development: Targeting the Brain

Success of drug development generally relies on selecting one or two most drug-like molecules from a large number of new chemical entities (NCEs) generated by combinatorial chemistry and subsequently filtered using in silico predictions. Drug-like properties include reliable bioactivity, favorable physical-chemical properties, and acceptable drug metabolism and pharmacokinetic (DMPK) profiles to enable “good” efficacy, availability, persistence, safety, and practicality in human (1). The use of highly sensitive and selective liquid chromatography tandem mass spectrometry (LC/MS/MS) assays during early in vitro and in vivo testing facilitates selection and advancement of one or two “best” compounds. Characterization of central nervous system (CNS) pharmacokinetics (PK), despite typically being performed during secondary or tertiary screening, is critical for the successful development of drugs targeting the CNS (e.g., anticonvulsants, antidepressants, anesthetics, antibacterials, and anticancer agents). The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) represent the main anatomical and biochemical (structural or functional) barriers between the peripheral circulation and the CNS. Thus, a key issue during early stage CNS-targeted drug development is lead compound penetrability of the BBB and/or BCSFB. This review will provide an overview of the application of LC/MS/MS in the nonclinical development of CNS drugs.

The priorities/needs of the pharmaceutical industry in drug delivery to the brain

Drug accessibility to the central nervous system (CNS) is the limiting factor in CNS drug development because many drugs do not penetrate the brain sufficiently. The highly restrictive endothelium of the brain capillary bed, i.e., the blood–brain barrier (BBB), and the protective epithelial layer of the choroid plexus, i.e., the blood–cerebrospinal fluid barrier (BCSFB), represent insurmountable obstacles for the brain penetration of many pharmacologically active compounds. Early assessment of the ability of drug candidate to penetrate the CNS is critical and crucial during the drug discovery process. A number of in vitro and in vivo approaches are available to aid in compound profiling: in silico prediction of BBB permeation, in vitro models of BBB and BCSFB, in situ and in vivo methods. Each technique has its own application with specific advantages and limitations; the strategy used by pharmaceutical research should be a combination of different models in order to obtain the best predictability to the clinical situation. Following the identification of brain penetration characteristics and the selection of the most promising compounds, the success of a CNS drug development program may be increased by enhancing drug delivery to the CNS. Strategies for CNS drug delivery may be classified as being invasive, pharmaceutical and biochemical.

Positron emission tomography and single-photon emission computed tomography in central nervous system drug development

Positron emission tomography and single-photon emission computed tomography in central nervous system drug development

Characterization of CNS disorders and evaluation of therapy using structural and functional MRI.

Modern drug development requires technologies that allow rapid translation from the preclinical to the clinical stage. It is obvious that non-invasive imaging modalities such as magnetic resonance imaging (MRI) will play a central role in this regard. This article reviews the use of structural and functional MRI readouts for characterization of central nervous system (CNS) disorders and evaluation of the efficacy of potential CNS drugs. Examples comprise dementia of Alzheimer's type, cerebral ischemia, and neuroinflammation covering both clinical and preclinical aspects. In these examples MRI has been used to obtain relevant structural information on brain atrophy, on the location and extent of ischemic brain areas, and on the number and distribution of demyelinated plaques. These structural data are complemented by readouts assessing the functional consequences associated with the pathomorphological changes. In the last decade, MRI has evolved into a standard tool for the development of CNS drugs. With regard to target-specific/molecular imaging applications MRI is limited by its inherently low sensitivity; complementary imaging modalities utilizing optical and radionuclear reporter systems will thus be required.

Human models as tools in the development of psychotropic drugs

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.

Genomics and dementia--new drug targets ahead?

Pharmacogenomics--the application of genomic technologies such as gene sequencing and gene expression analysis to drugs--is beginning to make its impact on central nervous system drug development. The mapping of genes (including their polymorphisms) and their expression in normal and disease states to discover new drug targets will also change the scenery of dementia therapeutics' development completely because it uses a "bottom-up" strategy, identifying genes whose expression is changed in dementia or by drug therapy. Drugs identified this way should be mechanistically novel, more potent and specific, and probably quicker to develop. Pharmacogenomics can however also greatly contribute to the improvement of drugs targeting currently known receptors and enzymes.

Positron emission tomography neuroreceptor imaging as a tool in drug discovery, research and development

Improved communication and cooperation between research-driven drug companies and academic positron emission tomography (PET) centers, coupled with improvements in PET camera resolution, the availability of small animal PET cameras and a growing list of neuroreceptor-specific PET tracers, have all contributed to a substantial increase in the use and value of PET as a tool in central nervous system drug discovery and development.