Qualitative measures that assess functional disability and quality of life in ALS.

BACKGROUND: Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials. METHODS: We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies. RESULTS: In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials. CONCLUSION: This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.

Strategies to Address Challenges in Neuroscience Drug Discovery and Development.

The paucity of novel drugs for neuropsychiatric indications contrasts with the remarkable recent advances in neuroscience research. We have identified 5 challenges the field needs to address and recommend potential solutions. First, we need to drive discovery efforts based on human data. Second, we need to think more carefully about animal models, embracing them as tools to test pathophysiological alterations. Third, we need to develop strategies to select more homogenous groups of patients in our clinical trials. Fourth, we need to develop and validate translational biomarkers, which can be used for pharmacodynamic assessments as well as for patient selection. Fifth, we need to adopt more reliable and objective measures to capture clinical efficacy. The tools that will allow these solutions to be implemented may already be in place but not routinely adopted or are still being developed. Overall, a change in mindset to adopt science- and data-driven paths is needed.

INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia.

Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.

The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial.

Several attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.

Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1.

The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively.

A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis.

Understanding patient clinical progression is a key gateway to planning effective clinical trials and ultimately enabling bringing treatments to patients in need. In a rare disease like amyotrophic lateral sclerosis (ALS), studies of disease natural history critically depend on collaboration between clinical centers, regions, and countries to enable creation of platforms to allow patients, caregivers, clinicians, and researchers to come together and more fully understand the condition. Rare disease registries and collaborative platforms such as those developed in ALS collect real-world data (RWD) in standardized formats, including clinical and biological specimen data used to evaluate risk factors and natural history of disease, treatment patterns and clinical (ClinROs) and patient- reported outcomes (PROs) and validate novel endpoints. Importantly, these data support the development of new therapeutics by supporting the evaluation of feasibility and design of clinical trials and offer valuable information on real-world disease trajectory and outcomes outside of the clinical trial setting for comparative purposes. RWD may help to accelerate therapy development by identifying and validating outcome measures and disease subpopulations. RWD can also make potential contributions to the evaluation of the safety and effectiveness of new indications for approved products and to satisfy post-approval regulatory and market access requirements. There is a lack of amalgamated information on available registries, databases, and other sources of real-world data on ALS; thus, a global review of all available resources was warranted. This targeted review identifies and describes ALS registries, biobanks and collaborative research networks that are collecting and synthesizing RWD for the purposes of increasing patient awareness and advancing scientific knowledge with the hope of expediting future development of new therapies.

Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation.

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1-50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

Quantification of ligand PET studies using a reference region with a displaceable fraction: application to occupancy studies with [(11)C]-DASB as an example.

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BP(D)=DVR-1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BP(D) that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [(11)C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test-retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BP(D) calculated either with plasma or with a reference input and high reproducibility.

Presynaptic 5-HT1A is related to 5-HTT receptor density in the human brain.

5-Hydroxytryptamine (5-HT or serotonin) is an important neurotransmitter for a number of brain functions and widely distributed throughout the brain. Physiological and pharmacological relationship between 5-HT1A receptors and serotonin transporter (5-HTT) in the regulation of 5-HT neurotransmission has now been documented. A relationship between 5-HT1A receptors and 5-HTT is also suggested by the pathophysiology of depression and the mechanism of action of antidepressants. We have scanned 42 healthy adults with both [11C] WAY-100635 and [11C] DASB to investigate the anatomical co-distribution of multiple serotonergic markers. We hypothesized that lower 5-HTT densities in the dorsal raphe nucleus (DRN) and limbic regions will be accompanied by lower 5-HT1A receptor density in the same regions, contributing to the 5-HT1A receptor desensitization. In addition, variations in DRN 5-HT1A receptor density can theoretically influence the density and/or function of other serotonin receptor subtypes and the 5-HTT consequent to changes in serotonergic tone. In a comparatively large sample of volunteers, we have shown that the relationship between 5-HT1A and 5-HTT PET indices was complex. We were unable to demonstrate robust, intra-regional relationships between 5-HT1A and 5-HTT densities. Inter-regionally, DRN 5-HT1A receptors were related to cortical (temporal and frontal regions) and paralimbic (insula), but not limbic 5-HTT. This latter finding may reflect differences in 5-HT tone between individuals, and highlights probable substrates sensitive to variations in DRN 5-HT function.