Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY)

Finger, Elizabeth; Berry, Scott M.; Cummings, Jeffrey L.; Coleman, Kristy; Hsiung, Ging-Yuek Robin; Feldman, Howard; Boxer, Adam L.

doi:10.1186/s13195-018-0427-2

Cited by 26 publications

(21 citation statements)

References 51 publications

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“…These have been used broadly in non‐AD trials including development of cancer and diabetes therapies [39,40]. Adaptive trials are being used in the BAN2401 trial, Dominantly Inherited Alzheimer Network–Treatment Unit [41], European Prevention of Alzheimer Disease initiative [42], and the Intranasal Oxytocin for Fronto‐temporal Dementia (FOXY) trial of intranasal oxytocin for frontotemporal dementia [43]. The trial of ABT‐089 pioneered the use of an adaptive design in AD [44].…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's disease drug development pipeline: 2019

Cummings

Lee

Ritter

et al. 2019

A&D Transl Res & Clin Interv

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Introduction Alzheimer's disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices. Methods We reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD. Results There are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase 1 trials. There is an increase in the number of agents in each phase compared with that in the 2018 pipeline. Nineteen agents in trials target cognitive enhancement, and 14 are intended to treat neuropsychiatric and behavioral symptoms. There are 96 agents in disease modification trials; of these, 38 (40%) have amyloid as the primary target or as one of several effects. Eighteen of the antiamyloid agents are small molecules, and 20 are monoclonal antibodies or biological therapies. Seven small molecules and ten biologics have tau as a primary or combination target (18%). Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Novel biomarkers (e.g., neurofilament light), new outcomes (e.g., AD Composite Score [ADCOMS]), enrollment of earlier populations, and innovative trial designs (e.g., Bayesian adaptive designs) are new features in recent clinical trials. Discussion Drug development continues robustly at all phases despite setbacks in several programs in the recent past. Continuing unmet needs require a commitment to growing and accelerating the pipeline.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's disease drug development pipeline: 2019

Cummings

Lee

Ritter

et al. 2019

A&D Transl Res & Clin Interv

Self Cite

650

619

View full text Add to dashboard Cite

show abstract

“…Adaptive designs may be used to optimize sample size, trial duration, and dose selection and have been successful in trials of chemotherapy and in trials for treatments of diabetes [155]. Adaptive designs are currently in use in the European Prevention of AD (E-PAD), the Dominantly Inherited Alzheimer Network-Treatment Unit (DIAN-TU), and a study of oxytocin in frontotemporal dementia [156]; broad exploration of the approach is warranted [157, 158].…”

Section: The Right Trialmentioning

confidence: 99%

The “rights” of precision drug development for Alzheimer’s disease

2019

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There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug-placebo difference. This low rate of success delays new treatments for patients and discourages investment in AD drug development. Studies across drug development programs in multiple disorders have identified important strategies for decreasing the risk and increasing the likelihood of success in drug development programs. These experiences provide guidance for the optimization of AD drug development. The “rights” of AD drug development include the right target, right drug, right biomarker, right participant, and right trial. The right target identifies the appropriate biologic process for an AD therapeutic intervention. The right drug must have well-understood pharmacokinetic and pharmacodynamic features, ability to penetrate the blood-brain barrier, efficacy demonstrated in animals, maximum tolerated dose established in phase I, and acceptable toxicity. The right biomarkers include participant selection biomarkers, target engagement biomarkers, biomarkers supportive of disease modification, and biomarkers for side effect monitoring. The right participant hinges on the identification of the phase of AD (preclinical, prodromal, dementia). Severity of disease and drug mechanism both have a role in defining the right participant. The right trial is a well-conducted trial with appropriate clinical and biomarker outcomes collected over an appropriate period of time, powered to detect a clinically meaningful drug-placebo difference, and anticipating variability introduced by globalization. We lack understanding of some critical aspects of disease biology and drug action that may affect the success of development programs even when the “rights” are adhered to. Attention to disciplined drug development will increase the likelihood of success, decrease the risks associated with AD drug development, enhance the ability to attract investment, and make it more likely that new therapies will become available to those with or vulnerable to the emergence of AD.

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“…In fact, if we assume that OXT modulates certain aspects of social cognition, it is reasonable to think that it does so regardless of diagnosis and/or condition. Thus, OXT could potentially improve the processing of emotional faces in neurodegenerative diseases such as Huntington's disease (43) and frontotemporal dementia (44,45). Further, OXT is currently being tested as treatment of social cognitive difficulties shown by healthy ageing individuals (46), where OXT does seem to improve certain aspects of social cognition (i.e.…”

Section: Oxytocin In Clinical Trialsmentioning

confidence: 99%

Oxytocin as Treatment for Social Cognition, Not There Yet

Erdozain¹,

Peñagarikano²

2020

Front. Psychiatry

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In a short time, oxytocin has progressed from being a regular hormone involved in parturition and breastfeeding to be possibly the neuromodulator that has gathered the most attention. Attributed many positive roles in the modulation of different aspects of social behavior, such as bonding, empathy, cooperation, trust, and generosity, as well as roles as a natural anxiolytic and antidepressant, the expectations on oxytocin becoming a treatment for a number of disorders with associated social deficits have dramatically raised over the last years. However, despite the field has been investigating oxytocin's role in social behavior for over twenty years, there are still many unknowns on oxytocin's mechanisms of action and efficiency and the increasing number of clinical trials administering oxytocin to different clinical groups seem to disagree in its properties and report in most cases conflicting results. This has led to some disappointment among researchers and clinicians as oxytocin might not be the miraculous molecule that works in a "one size fits all" fashion initially considered. Conversely, this down-side of oxytocin might merely reflect the complexity of its neurotransmission system. The current reality is that, although oxytocin seems to have potential therapeutic value, there are key questions that remain unanswered as to decide the optimal target groups and treatment course. Here, we present an overview on critical points regarding the oxytocin system in health and disease that need to be better understood to establish its therapeutic properties and to decide who could benefit the most from its treatment.

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Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY)

Cited by 26 publications

References 51 publications

Alzheimer's disease drug development pipeline: 2019

Alzheimer's disease drug development pipeline: 2019

The “rights” of precision drug development for Alzheimer’s disease

Oxytocin as Treatment for Social Cognition, Not There Yet

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