Better Approaches to Derisking Psychiatric Drug Development are Needed, Not New Funding Mechanisms.

BACKGROUND: The pulling back of large pharma from psychiatric drug development over the last 15 years has been a cause of concern. The uncertainty of success with any novel mechanism raises questions concerning whether current funding mechanisms for the various components of drug development need to be revisited. Alternatively, advances in neuroscience and translational methods may provide a sufficient incentive for continued private sector investment. METHOD: Narrative commentary drawing on personal positions in both NIH and Industry devoted to translation of CNS compounds from bench to bedside coupled with specific examples of efforts to improve the selection of compounds to take into large clinical trials. RESULTS: Strategies for increasing R&D productivity in the field of CNS drugs articulated over a decade ago have been implemented over the same period with pre-competitive consortia involved in developing the tools needed to show that before being taken into large trials adequate evidence of postulated brain effects are required. In parallel, the field and the FDA have focused much more on the search for domain specific treatments rather than those depending on traditional measures of efficacy in DSM disorders. NIMH programs such as RDoC and the "Fast-Fail" initiative are provided as efforts which influence and involve partnerships with industry. CONCLUSIONS: The evolution of the field over the last decade is such that there is a shared focus across sources of funding in the public sector, especially NIH brain institutes, on the tools needed to de-risk psychiatric drug development to the degree needed to encourage private sector investment in the clinical trials needed to advance potential new treatments for areas of greatest need. Expansion of funding for translational tool development will have the highest impact on delivering novel treatments.

Central Nervous System Trial Failures: Using the Fragile X Syndrome-mGluR5 Drug Target to Highlight the Complexities of Translating Preclinical Discoveries Into Human Trials.

PURPOSE/BACKGROUND: Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain function. Key design elements can be introduced into early-stage trials to get at this issue. METHODS/PROCEDURES: This commentary builds on a review of earlier clinical studies in Fragile X syndrome to explore the extent to which the chain of evidence is in place to allow for interpretation of the results as ruling in or out the utility of modulating one or another molecular target to treat this disorder. Recent and current biomarker studies in Fragile X syndrome occurring subsequent to the clinical studies are reviewed to see if they might address any chain of evidence gaps. FINDINGS/RESULTS: Despite the strong preclinical basis for targeting molecular mechanisms, the lack of efficacy seen in clinical studies remains uninterpretable, with regard to ruling in or out the utility of targeting the mechanism in a clinical population, given the absence of studies, which address whether doses of administered drug impacted the targeted brain mechanism. IMPLICATIONS/CONCLUSIONS: The value of pursuing clinical studies of compounds targeted to novel mechanisms in the absence of clinical pharmacological evidence of some anticipated mediating pharmacokinetic/pharmacodynamic signals is questionable. One or more biomarkers of a drug effect on brain function are needed to establish dose dependent CNS effects that allow one to interpret clinical results as ruling in or out a mechanism and providing a firm basis for continuing or not, as well as informing dose selection in any clinical efficacy trials. Initiatives to address this general need in pediatric psychopharmacology are highlighted.

Comparative analytical performance of multiple plasma Aß42 and Aß40 assays and their ability to predict positron emission tomography amyloid positivity.

INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aß) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aß assays. Statistical tests were performed to determine whether the plasma Aß measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aß in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. HIGHLIGHTS: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aß) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aß42/40 predicted amyloid positron emission tomography status better than Aß42 or Aß40 alone.

Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease.

INTRODUCTION: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. METHODS: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline. RESULTS: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.e., CN vs. MCI participants; AD pathology positive vs. negative defined by phosphorylated tau181/amyloid beta1-42 ratio; and clinical progressors vs. non-progressors). The rate of change of NPTX2 also significantly correlated with declining cognition. DISCUSSION: CSF NPTX2 concentration is a strong prognostic biomarker candidate of accelerated cognitive decline with potential use as a therapeutic target.

Perspective: The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partner Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for-profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific support to ADNI through the Foundation for the National Institutes of Health. The PPSB serves as an independent, open, and precompetitive forum in which all private sector and not-for-profit partners in ADNI can collaborate, share information, and offer scientific and private-sector perspectives and expertise on issues relating to the ADNI project. In this article, we review and highlight the role, activities, and contributions of the PPSB within the ADNI project, and provide a perspective on remaining unmet needs and future directions.

Finding new and better treatments for psychiatric disorders.

In contrast to most fields of medicine, progress to discover and develop new and improved psychiatric drugs has been slow and disappointing. The vast majority of currently prescribed drugs to treat schizophrenia, mood and anxiety disorders are arguably no more effective than the first generation of psychiatric drugs introduced well over 50 years ago. With only a few exceptions current psychiatric drugs work via the same fundamental mechanisms of action as first-generation agents. Here we describe the reasons for this slow progress and outline a number of areas of research that involve a greater reliance on experimental therapeutics utilizing recent advances in neuroscience to better understand disease biology. We exemplify the potential impact of these areas of research focus with several recent examples of novel agents that have emerged and which support our optimism that newer, more effective and better tolerated agents, are on the horizon. Together with existing drugs these newer agents and novel mechanisms could offer markedly improved functional outcomes for the millions of people still disabled by psychiatric disorders.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

INTRODUCTION: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. METHODS: Plasma samples from the Alzheimers Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. RESULTS: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. DISCUSSION: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes.

Shifting the trajectory of therapeutic development for neurological and psychiatric disorders.

Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized.

Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.

BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.

A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder.

Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.

BIOMARKERS AND NEUROBEHAVIORAL DIAGNOSIS.

Our current diagnostic methods for treatment planning in Psychiatry and Neurodevelopmental Disabilities leave room for improvement, and null results in clinical trials in these fields may be a result of insufficient tools for patient stratification. Great hope has been placed in novel technologies to improve clinical and trial outcomes, but we have yet to see a substantial change in clinical practice. As we examine attempts at biomarker validation within these fields, we find that it may be the diagnoses themselves that fall short. We now need to improve neuropsychiatric nosologies with a focus on validity based not solely on behavioral features, but on a synthesis that includes genetic and biological data as well. The eventual goal is diagnostic biomarkers and diagnoses themselves based on distinct mechanisms, but such an understanding of the causal relationship across levels of analysis is likely to be elusive for some time. Rather, we propose an approach in the near-term that deconstructs diagnosis into a series of independent, empiric and clinically relevant associations among a single, defined patient group, a single biomarker, a single intervention and a single clinical outcome. Incremental study across patient groups, interventions, outcomes and modalities will lead to a more interdigitated network of knowledge, and correlations in metrics across levels of analysis will eventually give way to the causal understanding that will allow for mechanistically based diagnoses.

The Alzheimer's disease neuroimaging initiative: perspectives of the Industry Scientific Advisory Board.

The Industry Scientific Advisory Board (ISAB) consists of representatives from the private companies and nonprofit foundations participating as sponsors of Alzheimer's Disease Neuroimaging Initiative (ADNI). Currently 21 companies are represented including pharmaceutical, imaging, and biotech concerns, and two foundations including the Alzheimer's Association. ISAB members meet regularly by teleconference or face-to-face at ADNI meetings and participate in the ADNI Core groups, all administered and organized by the Foundation for the National Institutes of Health. ISAB 'deliverables' include dissemination of information to sponsors, assisting in scientific review of protocols and results, initiation and consideration of "add-on" studies and analyses, and generation of consensus positions on industry priorities and concerns. Although positioned as an advisory body, ISAB also actively contributes to the ADNI mission of identifying biomarkers of disease progression.

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects.

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Abeta1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Abeta amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F-18 fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.

The NIMH 'Fast-Fail Trials' (FAST) Initiative: Rationale, Promise, and Progress.

In 2012, the US National Institute of Mental Health launched three clinical trial contracts under a new FAST initiative. The overall goal for these contracts (Fast-Fail Trials) was to focus early-stage trials, testing novel pharmacologic agents that target the central nervous system, on pharmacologic-based designs to objectively identify doses that produce central nervous system effects. The three contracts targeted different psychiatric populations: psychotic (FAST-PS), mood and anxiety (FAST-MAS), and autism spectrum disorders (FAST-AS). The FAST initiative was a first attempt for the National Institute of Mental Health to adapt an experimental medicine approach to its clinical trial portfolio. As the Fast-Fail trials implemented this new approach for the field, we present the rationale for each trial, design considerations, results, and how each one contributed new knowledge to the field of psychopharmacology; important lessons for pharma and biotech. Under the FAST initiative, the National Institute of Mental Health assembled research teams with a broad range of expertise, who developed and validated the outcome measures and study protocol, and conducted multi-site clinical trials, testing candidate compounds. In the FAST-PS contract, the team validated an imaging-based pharmacodynamic biomarker of the effect of ketamine in the brain that could be utilized in subsequent clinical trials. The initial FAST-AS study was an important first step in the design of early-stage target-engagement trials in autism spectrum disorder, suggesting that a resting electroencephalogram can be used as a pharmacodynamic measure in future studies. The FAST-MAS study showed that blocking the kappa-opioid receptor significantly affects functional magnetic resonance imaging ventral striatal activation in the monetary incentive delay task in anticipation of gain. Together, the outcomes of the FAST-FAIL trials demonstrated the importance of rigorously designed and informative central nervous system trials, including the value of pharmacodynamic measures in early-stage trials. Use of these measures furthered our knowledge about the relationship between specific molecular mechanisms, brain effects, and therapeutic effects in patients with mental illnesses.

Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS).

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.