Plasma and cerebrospinal fluid pharmacokinetics of vodobatinib, a neuroprotective c-Abl tyrosine kinase inhibitor for the treatment of Parkinson's disease.

BACKGROUND: Preclinical evidence suggests that c-Abl is critical in the pathogenesis of Parkinson's Disease (PD). Vodobatinib (K0706) is a potent, specific Abl kinase inhibitor currently being developed for the treatment of PD. In previously reported studies, nilotinib, a multikinase c-Abl inhibitor, did not show clinical activity as evidenced by no improvement of symptoms or the rate of decline after one to six months of treatment at the maximum permissible dose, presumably because of insufficient CNS penetration. Here we report clinical PK and safety data for vodobatinib. OBJECTIVES: To determine safety, plasma PK, and CSF penetration of vodobatinib in healthy volunteers and PD subjects following oral administration, and compare CSF levels to in vitro concentrations required for c-Abl inhibition relative to data reported for nilotinib. METHODS: Inhibition of c-Abl kinase activity and c-Abl binding affinity were first assessed in vitro. Healthy human volunteers and PD patients received various oral doses of vodobatinib once-daily for seven and fourteen days respectively, to assess safety, and plasma and CSF PK. RESULTS: In in vitro assays, vodobatinib was more potent (kinase IC50 = 0.9 nM) than nilotinib (kinase IC50 = 15-45 nM). Administration of vodobatinib 48, 192 and 384 mg to healthy subjects for 7 days yielded mean Cmax, CSF values of 1.8, 11.6, and 12.2 nM respectively, with the two highest doses exceeding the IC50 over the entire dosing interval. Cavg, CSF values were 6-8 times greater than the IC50. Comparable CSF levels were observed in PD patients. All doses were well tolerated in both cohorts. CONCLUSION: Based on achieved CSF concentrations, the potential for c-Abl inhibition in the brain is substantially higher with vodobatinib than with nilotinib. The CSF PK profile of vodobatinib is suitable for determining if c-Abl inhibition will be neuroprotective in PD patients.

Drug development for rare mitochondrial disorders.

Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications. The present challenge is translation of our collective knowledge of the molecular details underlying the pathophysiology of mitochondrial disorders into safe and effective therapies that are approved by the regulatory authorities. Molecular details permit precise diagnoses, but homogeneity is gained at the expense of limiting numbers of subjects for clinical trials and of small markets from which to recoup the considerable expense of drug discovery and development. The Food and Drug Administration recognizes that trial designs suitable for common diseases are often not feasible for rare disorders. They have developed a number of programs to facilitate development of novel therapies for such rare diseases, without compromise of regulatory standards. With advances in technology, including the use of biomarkers, replacement therapies and sophisticated trial designs, both biotechnology firms and, increasingly, large integrated pharmaceutical companies, are taking advantage of the opportunities in rare disorders. Precise molecular delineation of pathophysiology and of responsive patients has led to success rates with rare diseases that are significantly greater than those for common disorders. It appears likely, but not yet proven, that this may now be the case for rare mitochondrial disorders as well.

Importance and hurdles to drug discovery for neurological disease.

This is a critical time in neurotherapeutics. The prevalence of neurological disease, such as dementia, stroke, and peripheral neuropathy, is large and growing consequent to the aging population. The personal and societal impact of these disorders is enormous, and the number of novel therapies in the pipeline for these disorders has been contracting. Support for the development of neurotherapies must continue from the bench to their ultimate place at the bedside. Academic medicine must continue to play a critical role, in league with industry and government, in the development of novel neurotherapies desperately needed by an ever-expanding population. Critical steps include the identification and adoption of reliable, valid, and reproducible biomarkers to serve as primary endpoints in clinical trials of neurological disease.

Target-based drug discovery, genetic diseases, and biologics.

The last fifteen years have witnessed a major strategic shift in drug discovery away from an empiric approach based on incremental improvements of proven therapies, to a more theoretical, target-based approach. This arose as a consequence of three technical advances: (1) generation and interpretation of genome sequences, which facilitated identification and characterization of potential drug targets; (2) efficient production of candidate ligands for these putative targets through combinatorial chemistry or generation of monoclonal antibodies; and (3) high-throughput screening for rapid evaluation of interactions of these putative ligands with the selected targets. The basic idea underlying all three of these technologies is in keeping with Marshall Nirenberg's dictum that science progresses best when there are simple assays capable of generating large data sets rapidly. Furthermore, practical implementation of target-based drug discovery was enabled directly by technologies that either were originated or nurtured by Marshall, his post-docs and fellows. Chief among these was the genetic code. Also important was adoption of clonal cell lines for pharmacological investigations, as well as the use of hybridomas to generate molecular probes that allowed physical purchase on signaling elements that had previously been only hypothetical constructs. Always the pure scientist, Marshall's contributions nevertheless enabled fruitful applications in the pharmaceutical industry, several of them by his trainees. Both the successes and the shortcomings of target-based drug discovery are worthy of consideration, as are its implications for the choices of therapeutic goals and modalities by the pharmaceutical industry.

The ADNI Publication Policy: commensurate recognition of critical contributors who are not authors.

An efficient approach to certain types of biomedical research requires a scale that precludes involvement of all critical contributors in all aspects of experimental design, execution, and as well as writing of most, if not all, derived works. Guarantors of both the integrity of the data and of its subsequent analyses are required. When separate groups are responsible for each of these activities, each should be readily identifiable both in the primary publication and in all subsequent citations. We describe the publication policy of the Alzheimer Disease Neuroimaging Initiative (ADNI), its origins and its acceptance by the editorial and scientific communities.

Ablation of the locus coeruleus increases oxidative stress in tg-2576 transgenic but not wild-type mice.

Mice transgenic for production of excessive or mutant forms of beta-amyloid differ from patients with Alzheimer's disease in the degree of inflammation, oxidative damage, and alteration of intermediary metabolism, as well as the paucity or absence of neuronal atrophy and cognitive impairment. Previous observers have suggested that differences in inflammatory response reflect a discrepancy in the state of the locus coeruleus (LC), loss of which is an early change in Alzheimer's disease but which is preserved in the transgenic mice. In this paper, we extend these observations by examining the effects of the LC on markers of oxidative stress and intermediary metabolism. We compare four groups: wild-type or Tg2576 Aß transgenic mice injected with DSP4 or vehicle. Of greatest interest were metabolites different between ablated and intact transgenics, but not between ablated and intact wild-type animals. The Tg2576_DSP4 mice were distinguished from the other three groups by oxidative stress and altered energy metabolism. These observations provide further support for the hypothesis that Tg2576 Aß transgenic mice with this ablation may be a more congruent model of Alzheimer's disease than are transgenics with an intact LC.

Future drug discovery and development.

Drug discovery and development has evolved significantly over the last century. Extrapolation from current practice invites speculation about the future in four areas of particular interest. These include the range of therapeutic modalities; the methods for selection of drug targets; the interjection of translational medicine in between the traditional discovery and development phases; and the relationships between institutions. A major focus for the latter three developments is the shortcomings of current target validation. This personal view will be given from perspectives gained in large integrated pharmaceutical companies that are primarily focused on common disorders. Where appropriate, comparisons will be made to the development of treatments for rare Mendelian disorders.

The uses of biomarkers in drug development.

Although the value of "surrogate biomarkers" (strictly speaking, those biomarkers that can serve as surrogate primary endpoints in registration trials) is significant, such biomarkers are few. However, "nonsurrogate biomarkers" are increasingly being used to reduce the risks of drug development. Any given biomarker is usually useful for only one of four types of risk reduction: that associated with (1) an inappropriate dosing regimen; (2) enrollment of nonresponsive subjects into clinical trials; (3) an inability to detect an efficacy signal quickly and reliably in chronic disorders; or (4) delayed recognition of potential side effects and/or toxicity. A biomarker suitable for one purpose is usually not suitable for the other three. Although these considerations apply to all drug development, both the need and availability of appropriate biomarkers in each category vary between therapeutic areas. The focus is on diseases of the brain.

Pharmacologic interventions for stroke: looking beyond the thrombolysis time window into the penumbra with biomarkers, not a stopwatch.

BACKGROUND AND PURPOSE: The majority of pharmacological agents for stroke were developed based on the assumption that neurological deficits will be reduced upon the successful interruption of biochemical mechanisms leading to neuronal death. Despite significant evidence of preclinical efficacy, none of these agents succeeded. They either failed to demonstrate efficacy in the clinic or their development was halted for safety, strategic, or commercial reasons. SUMMARY OF REVIEW: This "neuroprotection strategy" has focused primarily on targets in the neurotoxic environment that occurs under ischemic conditions. In many cases, these agents were designed to tackle events that are known to start almost immediately after onset of ischemia, which is far before a realistic therapeutic time window opens for most, if not all, patients with stroke. In other instances, they were evaluated beyond a realistic timeframe in which one could expect significant salvageable tissue or penumbra to exist. Surprisingly, most of these agents were not evaluated in conjunction with strategies for improving perfusion to the affected tissue, indicating an overoptimistic assumption that neuroprotection alone could be sufficient to halt injury caused by an abrupt interruption of brain blood flow. CONCLUSIONS: We provide a constructive translational medicine perspective about how one could improve the drug development process with the hope that the probability for success can increase in our quest to establish a novel therapy for stroke.

Multimodal magnetic resonance imaging for assessing evolution of ischemic penumbra: a key translational medicine strategy to manage the risk of developing novel therapies for acute ischemic stroke.

The implicit aim of neuroprotection is to rescue neurons within distressed but still viable tissue, thereby promoting functional recovery upon neuronal salvage. The clinical failure of this approach suggests that previous efforts to develop stroke therapies lacked means to predict success or futility in pre-clinical and early clinical studies. A key translational medicine strategy that can improve predictability relies on imaging methodologies to map the spatiotemporal evolution of the ischemic penumbra. This could serve as a biomarker indicative of neuroprotective potential and could increase likelihood of success in clinical studies by allowing selection of patients who are most likely to respond to therapy.

Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1.

Disrupted-in-Schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated Disc1(tr) transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. Disc1(tr) transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in Disc1(tr) transgenic mice are consistent with findings in severe schizophrenia.

Drug development for CNS disorders: strategies for balancing risk and reducing attrition.

Disorders of the central nervous system (CNS) are some of the most prevalent, devastating and yet poorly treated illnesses. The development of new therapies for CNS disorders such as Alzheimer's disease has the potential to provide patients with significant improvements in quality of life, as well as reduce the future economic burden on health-care systems. However, few truly innovative CNS drugs have been approved in recent years, suggesting that there is a considerable need for strategies to enhance the productivity of research and development in this field. In this article, using illustrative examples from neurological and psychiatric disorders, we describe various approaches that are being taken to discover CNS drugs, discuss their relative merits and consider how risk can be balanced and attrition reduced.

The impact of preclinical drug safety on R&D productivity.

The Fifth International World Pharmaceutical Congress was held in the Philadelphia Convention Centre during May 23 - 25 2006. In addition to exhibits and three plenary presentations, there were six concurrent sessions. In this report the author summarises some of the highlights of the conference entitled 'The impact of preclinical drug safety on R&D productivity'. This focused session gave a broad overview of the present state and future directions of drug safety assessment, both from a technical and organisational perspective.

Translational research in central nervous system drug discovery.

Of all the therapeutic areas, diseases of the CNS provide the biggest challenges to translational research in this era of increased productivity and novel targets. Risk reduction by translational research incorporates the "learn" phase of the "learn and confirm" paradigm proposed over a decade ago. Like traditional drug discovery in vitro and in laboratory animals, it precedes the traditional phase 1-3 studies of drug development. The focus is on ameliorating the current failure rate in phase 2 and the delays resulting from suboptimal choices in four key areas: initial test subjects, dosing, sensitive and early detection of therapeutic effect, and recognition of differences between animal models and human disease. Implementation of new technologies is the key to success in this emerging endeavor.