CereSpir Incorporated, a company with a novel approach to treat neurodegenerative diseases by harnessing the innate immune system, has submitted a Special Protocol Assessment (SPA) request to the US Food and Drug Administration (FDA) to initiate detailed design discussions for a phase 3 clinical study of CSP-1103 to test its ability to slow the progression of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD).

The SPA request includes the proposed phase III study protocol, statistical analysis plans and briefing materials along with specific questions from CereSpir to facilitate a meaningful dialogue with the FDA on the proposed study design.

Following receipt, the FDA will determine the appropriateness of the SPA request and may take up to 45 calendar days to provide comments to CereSpir. The nature and extent of comments received will determine the need for any additional rounds of review and/or a formal meeting. The FDA’s assessment of the SPA request, and all related feedback, will inform the development of CSP-1103 in slowing the progression of MCI due to AD.

The proposed phase 3 clinical trial is designed as an adequate and well controlled, double-blind, adaptive design, placebo-controlled multinational study of CSP-1103 administered to subjects with MCI due to AD who have biomarker evidence supporting this condition. It will determine the ability of the drug to slow the rate of clinical decline. In addition, the effects of the drug on a number of biomarkers related to important pathophysiological processes underlying AD will be evaluated in subgroups of subjects.

The primary objective of the study will be to evaluate the effects of CSP-1103 compared to placebo on clinical decline in subjects with MCI due to AD and who are also positive for amyloid ß (Aß) biomarker. Secondary objectives of the study will be to evaluate the effects of CSP-1103 on daily life function, a pre-specified biomarker to support the hypothesis that CSP-1103 is a disease-modifying drug, and safety measures.

AD is the most common cause of dementia and represents an enormous and growing global public health challenge. It is a uniformly fatal neurodegenerative disorder with no cure or substantially effective treatment. AD currently affects more than 5 million Americans, 7 million Europeans and in total, about 44 million people worldwide according to the most recent report by the Alzheimer’s Association. Mild Cognitive Impairment (MCI) causes cognitive changes that are serious enough to be noticed by the individuals experiencing them or to other people, but the changes are not severe enough to interfere with daily life or independent function; therefore, they do not meet diagnostic guidelines for dementia. Just over half of people with MCI progress to an AD dementia diagnosis. This proportion is significantly increased in people who also have measurable brain amyloid. Thus people who have this combination are considered to have MCI due to AD. Although several symptomatic treatments have been developed and approved in various countries for AD dementia, they result in only small cognitive and functional benefits in this disease stage that are not sustained.

Acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonists (memantine) have a minimal impact and target late aspects of the disease. Although these treatments and others have been tested in the pre-dementia disease stage, none have been approved. Moreover, no truly disease-modifying treatments have been approved for either the early or late disease stages.

CSP-1103 is an orally available, small molecule which is the first among a new class of pharmacologic agents, combining the reduction of pro-inflammatory cytokines and enhancement of phagocytosis. Both properties should be therapeutically beneficial for AD, and the combination might be especially valuable. The phase 2 clinical programme generated preliminary safety and efficacy data in approximately 100 people half of whom received CSP-1103 for up to 2 years.

Data from this study were presented at the Alzheimer’s Association International Conference in 2013 and 2014. CSP-1103 has been shown to inhibit brain amyloid beta (Aß) plaque deposition, reduce tau pathology and neuro-inflammation and reverse associated memory deficits in AD transgenic mouse models. These changes associated with the observation that CSP-1103 can restore normal microglial function which is impaired in AD by increasing phagocytosis and decreasing production of pro-inflammatory cytokines. Chronic dysfunction of microglia is increasingly believed to play an important role at the very beginnings of AD with several newly discovered genetic risk factors supporting this idea. These effects of CSP-1103 may translate into preventing the memory loss that is the hallmark of MCI due to AD.