Authors: Ellen Clarke
For many years neuroinflammation has been thought to be a key player in the pathogenesis of Alzheimer’s disease (AD). However, in the early 2000’s a number of anti-inflammatory treatment studies yielded negative results. Recently there has been renewed interest in the role of neuroinflammation as a driver of AD, and its potential as a therapeutic target. This was apparent at the 8th International Conference on Clinical Trials for Alzheimer’s Disease (5–7 November 2015, Barcelona, Spain), where anti-inflammatory treatments took centre stage.
“The field languished for at least a decade, until three years ago when intriguing findings about genetic risks for AD clustering around the innate immune system began to emerge, pointing to defects driving pathology,” commented Richard Margolin from CereSpir, Inc. (NY, USA). Now, he explained “the study of neuroinflammation in AD is expanding by leaps and bounds.”
Researchers are still trying to fully understand the role of the innate immune system in AD. Importantly it is now understood that the role of astrocytes and microglia alters during the course of the disease. In the healthy brain, microglia possess a neuroprotective role, demonstrating a phagocytic capacity. However, in the AD brain they begin producing huge amounts of cytokines that induce tissue damage, no longer maintaining their protective phagocytic role.
Researchers have been investigating the reasons for earlier failed trials. Possible explanations include the wrong choice of molecular targets, incorrect trial designs and timing of drug administration.
Findings about the innate immune system however are now beginning to be translated into treatment strategies: “One strategy is to reduce cytokine production,” Margolin explained, “but our approach is to pair that with enhancement of phagocytosis, because we think both are important and the combination could be synergistic. Preclinical studies showed beneficial effects for our drug CSP-1103 on both properties, and cytokine reductions were also seen in healthy volunteers and patients with mild cognitive impairment.”
Well-designed trials for novel anti-inflammatory drugs will be important to their evaluation. “We’ll need appropriate biomarkers and a good understanding of the link between proposed pharmacological mechanisms and clinical effects,” commented Margolin. “For trials, this means information about the population most likely to benefit, the appropriate treatment duration, and the best readouts.” Recent evidence suggests that the cellular and molecular features of neuroinflammation may be associated with different stages of the disease, which may consequently affect the timing of when an intervention will be most effective.
CereSpir is currently planning its first late-stage trial of CSP-1103, which researchers will conduct in patients with mild cognitive impairment due to AD. “Our trial will use an adaptive design because that approach enables a certain degree of flexibility, for example, in determining the final sample size for a trial,” Margolin explained. “Regulatorily acceptable adaptive designs are attractive in late-stage development because they can potentially help accelerate the process, which is very important, given the long treatment periods required at this time for disease-modifying AD drugs.”
Source: 8th International Conference on Clinical Trials on Alzheimer’s Disease press release