Schizophrenia Bulletin Advance Access originally published online on September 8, 2005
Schizophrenia Bulletin 2005 31(4):816-822; doi:10.1093/schbul/sbi051
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Developing Drugs for Cognitive Impairment in Schizophrenia
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285
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Abstract
IntroductionThere are strong data suggesting that improvement in the cognitive impairment associated with schizophrenia will contribute to enhanced functional outcomes for patients with this illness. Measurement and Treatment Research to Improve Cognition in Schizophrenia was established to provide a pathway for developing and registering potential cognitive-enhancing agents for this condition by addressing issues related to the content of the cognitive assessment battery and the clinical design features to be used in registration studies. This article examines key challenges related to the actual clinical development of cognitive-enhancing agents. These challenges include improving the probability of technical success and attrition rates of candidate molecules, establishing better animal models of human cognition, and developing biomarkers to decrease development costs and increase the speed of the clinical discovery process. Biomarkers are important for molecular target validation, dose selection, surrogate end points, and population segmentation. Examples of approaches for the development of agents for cognitive impairment associated with schizophrenia are discussed. It is concluded that close collaboration among academia, the National Institutes of Health, regulatory bodies, and industry will be important to advance the goal of developing drugs for this important condition.
Keywords: functional outcomes / biomarkers / surrogate end points / acetylcholine / targeted therapeutics
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Introduction |
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Since the advent of antipsychotic drugs nearly 5 decades ago, great strides have been made in the treatment of schizophrenia. First-generation antipsychotic drug therapy has significantly improved relapse rates and positive symptoms. Clozapine, the first second-generation, or atypical, antipsychotic agent, has superior efficacy in treatment-resistant patients compared to first-generation agents,1–2 and other atypicals have a more favorable tolerability profile, particularly for extrapyramidal symptoms, compared to the first-generation drugs.3 For the majority of schizophrenic patients, good control of positive symptoms and the ability to reside in the community are possible.
Despite these advances, the overall functional and quality of life outcomes for patients with schizophrenia remain poor. Full employment and independent living are seen in less than 20% of patients.4 Social functioning is also marginal for the majority of patients. The overall poor functional prognosis for schizophrenia calls for a new pharmacotherapy for this illness with the development of novel agents with unique pharmacological effects.
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Cognition as a Target for Drug Development |
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One approach to the development of new agents for schizophrenia to improve functional outcomes is focusing on cognitive impairment. There is a large body of literature indicating that cognitive impairment is pervasive and a core psychopathological component of schizophrenia.5–8 The main cognitive domains affected include verbal and working memory, executive functioning, sustained attention, visual-spatial performance, and processing speed. Importantly, cognitive deficits have been implicated as a major impediment to gaining enhanced functional status,9 and a direct relationship has been demonstrated between cognitive impairment and poor functional outcomes.10–13 Thus, it is postulated that improving cognitive dysfunction will lead to enhancing functional outcomes. Current treatments to test this hypothesis are somewhat limited in their ability to improve cognition. There is support that the second-generation agents have better cognitive effects compared to first-generation neuroleptics, but the overall effect sizes are modest.14–15 Other approaches to cognitive remediation have yielded mixed results.16
The data above indicating that schizophrenia is associated with cognitive impairment and that these impairments are related to poor functional outcomes stimulated the development of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) to begin to lay the groundwork for the development and registration in the United States of cognitive-enhancing agents for cognitive impairment associated with schizophrenia (CIAS). To achieve this goal, numerous issues must be addressed, and substantial challenges, overcome.
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Contributions of MATRICS |
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The contributions of MATRICS are many and include establishing a dialogue among key stakeholders in the drug-development process—the Food and Drug Administration (FDA), academia, the National Institutes of Health (NIH), and industry. A process facilitated by the RAND Corporation to drive the groups to consensus and to achieve specific objectives was also successfully employed. In addition, MATRICS established CIAS as a "legitimate" target for drug development from a regulatory perspective in the United States. A standard cognitive battery to be used as a primary outcome measure in registration trials was achieved. A clear pathway for the clinical development of drugs for CIAS was established, which included gaining consensus on critical design elements for the clinical plan to support registration. These design elements include requiring co-primaries (i.e., a cognitive battery and a functional outcome measure) and a minimum duration of 6 months. Patients will need to be clinically stable (i.e., 8 to 12 weeks, residual phase) prior to randomization. The important issue of "pseudospecificity" was addressed for clinical designs that test the efficacy of "add-on" agents to existing antipsychotic therapy. Pseudospecificity refers to proving that the treatment effect is not secondary changes in other symptoms. For example, if psychosis and cognition both improved during treatment, it would be difficult to prove there was a direct treatment effect on cognition. In an add-on design to antipsychotic drugs, psychosis change would be accounted for prior to the "add on" of the experimental cognitive-enhancing agent. The issue of pseudospecificity, however, was not resolved for potential cognitive enhancers to be used as monotherapies. From an industry perspective, the importance of the above accomplishments to encourage investment in programs to develop drugs for CIAS cannot be emphasized too much.
Whereas the contributions of MATRICS have been substantial, there are key questions relevant to CIAS that persist. These questions include the following:
- Does CIAS warrant remediation irrespective of functional impact? It can be argued that cognitive impairment alone (independent of functional impact) is associated with substantial clinical burden for individual patients, and the alleviation of this impairment should be a clinical priority irrespective of collateral effects on functioning.
- If cognitive improvement creates the "readiness" for functional improvement, will psychosocial therapies be required to demonstrate a functional effect?
- If functional improvement is the "golden ring" (i.e., the ultimate therapeutic goal), should drug development focus directly on functional outcome as opposed to CIAS?
- Given that schizophrenia onset frequently occurs during the preadult period (i.e., teenage years), elements of adult functioning may not have been acquired prior to illness onset; therefore, how is an effect demonstrable on these functions?
- How will average clinicians assess cognitive impairment in their practices and know if a cognitive improvement has occurred and is substantial enough to justify continued treatment with a cognitive-enhancing agent?
- How will functional change be assessed? Better defining the functional outcome measure will help resolve some of the key issues mentioned above. Eli Lilly and Company has established an academic collaboration to develop a functional scale specific for drug trials in schizophrenic populations. The instrument follows a semistructured interview and requires about 30 minutes to administer. The domains included in the instrument are living situation, role functioning, basis and instrumental activities of daily living, and social and recreational activity. Field-testing to assess psychometric properties has been completed in stable schizophrenic patients and their informants, with finalization of the instrument anticipated for 2005.
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Challenges of Drug Development for CIAS |
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Now that the critically important pathway for developing and registering drugs for CIAS has been established, the actual challenges of drug discovery and development must be addressed. Bringing drugs to market is a daunting task that has become even more challenging over recent years. The number of new drug applications submitted to the FDA in recent years has decreased (figure 1), while costs of developing new molecular entities (NMEs) are skyrocketing (figure 2). The current cost per NME is approximately $1.2 billion (which includes development costs and costs of capital). The time per NME development from the earliest discovery efforts through FDA approval and market launch has also increased to approximately 15 years. It has been argued that 1 of the reasons for the increasing development costs and time is the fact that disease targets today for innovative, first-in-class treatments for areas of greatest unmet medical need, such as Alzheimer's disease and obesity, are more challenging from a scientific perspective than drug targets in the past (i.e., the "low hanging fruit has been picked"), thus leading to greater rates of attrition. It has also been argued that the regulatory demands for drug approval are increasing, leading to larger sample sizes and trials of longer duration prior to approval, as well as requirements for greater postapproval clinical trial commitments. Further, it has been suggested that reimbursement pressures on marketed drugs are calling for more clinical data at product launch to bolster the risk/benefit analysis, which is increasing development costs.
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Once a "candidate decision" has been made (i.e., the point at which a decision is made to progress molecules from the laboratory to the clinic for first human exposure), 90% of these candidates fail to achieve successful registration as a new drug (figure 3). The primary reasons for the high attrition rates include uncovering prohibitive toxicology/safety findings and the failure to achieve efficacy. The highest attrition rates occur during first proof of concept for efficacy in phase II. Success rates are particularly low in the development of central nervous system (CNS) drugs (figure 4), primarily because of the lack of validated animal models and surrogate end points for these diseases and a less advanced understanding of basic disease pathophysiology. This is germane for CIAS in that there should be a realistic understanding that the failure rate (and associated development costs) of candidate drugs for CIAS will likely be very high and that, therefore, numerous candidates will need to be tested in order to successfully register and launch 1 agent for this condition.
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Improving the Probability of Technical Success |
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The most important challenge to be addressed in developing drugs for CIAS is improving the probability of technical success. Probability of technical success for putative drugs for CIAS will be enhanced in 3 ways. First, it is critical to advance the basic scientific understanding of the biology of cognition, including neurochemical circuitry and genomic determinants. Second, establishing better animal models of cognitive impairment is an important step forward that would allow the screening of numerous compounds and improve selection criteria for a development candidate prior to introduction in human studies. The third key element to improve the probability of technical success in developing drugs for CIAS is the validation of biomarkers that could be used throughout the clinical development process.
A key challenge is designing clinical experiments that "uncover" a molecule's likelihood of success as early as possible in clinical development. Eli Lilly and Company uses the phrase "quick win, quick kill." This refers to the notion of pulling attrition forward in the clinical development process so that molecules that are destined to fail, fail as early as possible (e.g., phase I or early phase II) and molecules that have the greatest potential for successful registration have accelerated development programs. It is critical from a cost and resource-allocation perspective that a molecule's likelihood of success is accurately predicted as early in development as possible. Biomarkers are a critical element in the "quick win, quick kill" strategy.
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Biomarkers: A Key Component to Develop Drugs for CIAS |
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The definition of a biomarker is any characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic process, or pharmacologic response to a therapeutic intervention (NIH Definitions Working Group, proceedings of NIH-FDA conference, 1999). The potential role of biomarkers in clinical development includes target validation, dose selection, surrogate end points, and population segmentation.
Target Validation
There are 2 types of biomarkers related to target validation: disease-specific and drug activity biomarkers. Disease biomarkers are used to characterize disease predisposition, which includes phenotypic and genotypic markers, disease diagnoses that are used for patient selection, and disease progression. Drug activity biomarkers are used primarily to determine if the drug in question is interacting with its target (e.g., receptors, transporters), its off-rate characteristics as it leaves its target, and any potential relevant downstream or nontarget activity.
Fundamental questions that have been particularly vexing for CNS drug development include the following: Is the experimental drug entering the human brain, and if so, in what quantities? If the drug is entering the brain, is it reaching its target, and if so, at what concentrations? A good example of biomarker application to assess target validation in CNS drug discovery is in the development of neurokinin-1 (NK1) antagonists. This novel class of drugs was first purported to be a potential treatment for depression, although subsequent validation for this condition was not achieved. Other possible indications include anxiety and pain. The initial challenge facing NK-1 clinical development related to brain uptake and receptor-saturation characteristics. In the past, clinical trials would be based on inferences from animal experiments, and large trials would be required to assess clinical tolerability and initial suggestions of efficacy. A positron emission tomography (PET) neurotracer was developed specifically for NK-1 receptors that were then used to quantify brain uptake and receptor occupancy.17 These data then guided the selection of the appropriate molecule for future clinical trials.
Dose Selection
Choosing the correct dose to test initial efficacy and safety questions in proof of concept clinical trials, to then use in pivotal phase III registration trials, and to ultimately bring to the market is a key issue that is particularly challenging in CNS drug development. For example, if a phase II proof of concept trial fails to demonstrate efficacy, it is critically important to know if the failure was because of an intrinsic limitation of the molecule as opposed to the use of subtherapeutic doses. It has commonly occurred that the appropriate clinical dose has not been defined early in clinical development, which then leads to very large phase III trials with multiple dosing arms. Entering phase III trials without clarification of the appropriate dose significantly increases the risk of phase III attrition.
The above example of the development of NK-1 antagonists is also a good example of how a biomarker strategy, in this case a PET neurotracer for NK-1 receptors, can be used to address key questions related to dose finding at the very beginning of clinical development. Receptor occupancy studies that determine receptor saturation levels will provide the assurance that an adequate dose is being used in proof of concept studies to test the primary clinical outcome questions and that failure to demonstrate efficacy is not because of subtherapeutic dosing.
Surrogate End Points
A surrogate end point is a biomarker intended to substitute for a clinical end point. An example of a surrogate end point for oncology drugs being developed for brain tumors such as glioblastoma is magnetic resonance imaging (MRI) evidence of tumor shrinkage as opposed to the traditional clinical end points of survival rates. In early proof of concept studies this MRI marker would be used to make the key decision whether to proceed to pivotal phase III trials. This approach allows for smaller studies with shorter durations. FDA approval would be required to use this surrogate end point as the primary outcome measure in phase III trails to register the drug. Other examples of surrogate markers are fasting glucose and hemoglobin A1C used in the development of drugs for diabetes and plasma LDL and HDL cholesterol levels for developing statins.
An example of a surrogate end point in the development of drugs for CIAS is functional brain-imaging scans of selective brain regions involved in specific cognitive functions (e.g., prefrontal cortex, hippocampus). Nonbiological surrogate end points may be particularly useful as proxies for functional outcomes. Examples include tasks that mimic work function, such as assembling a simple appliance, which could be used in a controlled laboratory setting, as opposed to the high hurdle of demonstrating true functional gain, such as gainful employment, which would likely require very large sample sizes and long durations of treatment. Again, this use of surrogates in early proof of concept studies allows for smaller studies of shorter duration and then can be used to make a "go/no go" decision related to progressing the experimental drug to large phase III studies. As noted above, FDA approval would be required to use surrogates such as a work proxy as primary outcome measures in the pivotal registration trials as opposed to actual functional gains.
Population Segmentation—"Right Drug, Right Patient"
Using biomarkers to identify homogeneous patient populations is important for both the drug-development process and the identification of appropriate patients for clinical treatment after market launch. As noted above, the cost of developing NMEs is rapidly escalating. A major reason for the increasing cost is the growing size and duration of phase II and III studies. Utilizing biomarkers to a priori identify more homogeneous patient populations to enroll in phase II/III studies will decrease the variance in clinical response and thereby increase statistical power, leading to smaller sample sizes.
A hypothetical example of population segmentation in CIAS drug development is the use of a genomic marker such as the functional polymorphism in the catechol-O-methyltransferase (COMT) gene. This polymorphism, involving a single nucleotide polymorphism at the valine-158-methione locus, affects the enzyme activity of extracellular dopamine catabolism18–19 and appears to uniquely affect prefrontal dopamine function.20 Numerous studies have now shown that the COMT variant predicts neurocognitive performance in patients with schizophrenia21–23 and well relatives of patients with schizophrenia.24 Bertolino et al. have found a significant interaction between COMT genotype and the effects of the atypical antipsychotic drug olanzapine on prefrontal cortical function.25 Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. Thus, COMT genotyping could be considered in a proof of concept trial of a potential cognitive-enhancing agent to define a more homogeneous patient sample.
The "holy grail" of drug development is to use biomarkers to identify segments of the target patient population that will derive maximal benefit (optimal efficacy and/or minimal side effects) and to use them by clinicians to select patients for treatment. Historically, drugs were developed to treat a disease, such as schizophrenia or major depression, and it was up to the clinician by trial and error to ferret out the responders from the nonresponders and the patients who tolerated the agent from those who did not. Population segmentation seeks to identify the right patient for the right drug prior to initiating the trial by using segmentation biomarkers.
This so-called targeted therapeutics has become mainstream in the development of drugs for cancer.26–27 This is feasible in oncology in part because tumor tissue is directly accessible and used for genetic profiling and protein expression. Several oncology drugs, including Herceptin, Iresa, Rituxan, and Gleevec, are marketed with genomic test kits to identify the appropriate patient segment for these agents. The Gleevec "story" is informative for developing targeted therapeutics.28–29 In brief, in 1960 a shortened chromosome was noted in patients with chronic myeloid leukemia (CML) that was termed the "Philadelphia chromosome." Over the next 2 decades, it was learned that 2 ends of the shortened chromosome produce a cancer-causing protein termed Bcr_abl. In 1986–1987, Bcr_abl was shown to be a tyrosine kinase, and a mechanism whereby this protein jams the cellular signal, preventing white blood cell production, was elucidated. Following this discovery, the search for a drug that blocks Bcr_abl was undertaken, with a major challenge being that there are literally hundreds of tyrosine kinases in human cells. In 1992 Gleevec was synthesized, with first human exposure occurring in 1998 in academic–industry collaboration. The results were very encouraging, and Gleevec was "fast-tracked" by the FDA, with approval for CML occurring in 2001 along with a genetic test kit for the Philadelphia chromosome. The development of Gleevec is informative for the future of targeted drug discovery, demonstrating the importance of the evolution of scientific discovery and academic–industry collaboration. It also demonstrates the long timelines between the discovery of disease genetic markers, the elucidation of disease-causing proteins, and the eventual drug development to combat the disease.
The biology of human cognition and an understanding of the pathophysiological mechanisms in CIAS are in their infancy. Consequently, the likelihood of developed targeted therapies for patients with CIAS based on genotyping or other biomarkers in the near future is not likely. However, as science progresses in this area, target therapeutics may become a reality.
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Candidates for CIAS Drug Developments |
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Numerous pharmacological strategies have been proposed for developing agents to treat CIAS. The proposed neurochemical platforms include dopamine, norepinephrine, glutamate, and acetylcholine.16 In fact, any of the numerous neurochemical systems implicated in cognition are reasonable candidates to consider. One example relates to cholinergic mechanisms, as there are multiple lines of evidence providing support for central cholinergic systems to be considered in drug development for CIAS. First, there is strong preclinical and clinical evidence linking acetylcholine function and memory (including induction of memory deficits with acetylcholine inhibitors and enhancing memory with acetylcholinesterase inhibitors).30–32 In addition, several schizophrenia postmortem studies have demonstrated reductions in muscarinic receptors.33–36 Raedler and associates have assessed muscarinic receptor availability using in vivo 123Iodoquinuclidinyl benzilate single photon emission computerized tomography scanning in unmedicated schizophrenic patients and found significant reductions in patients compared to controls.37 Bymaster et al. report that a novel compound with partial agonistic effects at muscarinic M-2 and M-4 receptors demonstrated surprising preclinical effects that mimicked antipsychotic drug actions.38 Xanomeline is another muscarinic agonist with relatively high selectivity for M-1 and M-4 receptors that demonstrates antipsychotic-like properties in animal models.39 Moreover, xanomeline was first developed as a potential treatment for Alzheimer's disease, and in early clinical trials it demonstrated efficacy for both cognitive impairment and psychosis in these patients.40 However, significant side effects including nausea and vomiting prevented further consideration of xanomeline in this population. Xanomeline was later examined as a monotherapy treatment in chronic schizophrenia patients in a small double-blind placebo-controlled trial. The results suggest that xanomeline has evidence for improvements in both psychosis and cognitive impairment. Although preliminary because of the small sample size, this proof of concept study provides support to further consider muscarinic augmentation as a potential therapeutic for CIAS.
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Conclusion |
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Because of the MATRICS process, a significant step forward has been made toward the ultimate goal of providing effective treatments for cognitive impairment associated with schizophrenia and improving the overall functional status for patients with this illness. While the pathway for developing such agents is beginning to be established, substantial progress is needed before the first such drug is available for clinical use. It will be imperative that the interaction among key stakeholders—NIH, academia, regulatory agencies, and industry—that has worked so well in MATRICS be continued in collaborative frameworks throughout the future drug-development process. Perhaps the area of progress that is most critically important in order to accelerate drug development for CAIS is in the basic science of human cognition. Another key area where progress is needed is the development of animal models of CIAS. This would allow for the rapid screening of interesting molecules, leading to the better selection of candidates for clinical trials. In addition, advances in biomarker and surrogate end points would facilitate CIAS drug developments. Once agents have been found that successfully treat CIAS, education and training for practicing clinicians on how to detect and assess change in cognitive deficits will be needed. All of these areas are ripe for collaborative activities.
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Footnotes |
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To whom correspondence should be addressed; tel: 317-277-9222, fax: 317-277-2025, e-mail: a.breier{at}lilly.com.
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