Pipeline Report - Neuronal alpha 7 nicotinic receptors: Candidates for the treatment of Alzheimers disease and Schizophrenia

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Neuronal nicotinic receptors (nAChR) have been gaining interest over the past decade as a potential target for both therapeutic and, more recently, imaging agents. Various peripheral disorders such as inflammation are now being encompassed by nicotinic receptor drug discovery which has, in the past focused on CNS indications.

The first α7 nAChR agents are nearing the market. This report describes the proof of concept supporting the development of this class specifically for Alzheimer’s disease and schizophrenia.

α7nAChRs are selectively expressed in the brain, particularly in regions implicated in cognitive function and especially Alzheimer’s disease and schizophrenia.

A large body of evidence supports the development of α7nAChR ligands for the treatment of Alzheimer’s disease. Nicotinic agonists may directly block the deleterious effects of αβ42 mediated through α7nAChRs. The efficacy of α7nAChR seen in trials to data is however more likely to reflect the enhancement of physiological cognitive pathways and domains which are compromised during Alzheimer’s such as working memory are stimulated by α7nAChR agonists.

The most popular approach to α7 nAChR drug development for Alzheimer’s disease has been to develop partial agonists although some of these partial agonists may actually be co-agonists. This new concept involves ACh docking in one receptor binding site and the agonist binding the second site. This results in synergy ACh and ACh esterase inhibitors (eg Donepezil).

Schizophrenia is associated with multiple overlapping symptoms including positive symptoms (eg psychoses); negative symptoms (eg flatness) and cognitive disorders. Treatments are only available for positive symptoms even though negative symptoms and cognitive impairment significantly reduce the patient’s quality of life.

Seven domains of cognition are deficient in schizophrenia. These include: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, processing speed, reasoning and problem solving and social cognition. α7 nAChR involvement has been reported for most of these domains supporting the development of this class for CIAS.

A number of pharmacological options exist for the development of α7nAChR ligands for CIAS. Most promising, but underutilized, may be allosteric modulators (PAMs) as this approach can upregulate cholinergic pathways without subjecting the α7 nAChR to continuous stimulation and potential toxicity.

A total of 8 α7 nAChR candidates are currently in the clinic. Of these, 2 Phase 2 candidates are for non-CNS indications (diabetes and asthma; TC-6987 and ASM-024) while Neuroderm’s ND0801 is in Phase 2 development for ADHD. ND0801 appears to be a nicotine formulation. This leaves 4 candidates in Phase 2 and 1 in Phase 1 development for CIAS and/or Alzheimer’s disease. We believe that the Phase 1 candidate, XY 4083 has been terminated with its parent company, Xytis possibly no longer trading.

The 4 Phase 2 candidates are RG3487 (Roche; Alzheimer’s); EVP6124 (En Vivo; Alzheimer’s and CIAS); TC-5619 (Targacept; CIAS as well as ADHD) and AQW051 (Novartis; CIAS). Very little is known about AQW051.

EVP6124 and RG3487 lead the α7 nAChR field. Both are described as co-agonists but RG3487 has additional 5HT3 antagonist activity. A Phase 2b study of RG3487 in Alzheimer’s is due to read out in May 2011 while EVP6124 is in Phase 2b trials for both Alzheimer’s and CIAS. The Alzheimer’s study should read out at around the same time as the RG3487 study in mid-2011; the CIAS study should read out a little earlier. En Vivo could gain first in class status although the company does not have a development partner outside of Asia and this could delay matters.

TC-5619 currently sits a little behind EVP6124, in Phase 2a for CIAS (as well as ADHD); it is not currently competing with RG3487 as the two are being developed for different indications. This may change if Alzheimer’s disease is adopted as a target. Like EVP6124, TC-5619 does not antagonize the 5HT3 receptor. One intriguing difference is that TC-5616 appears to have activity against cognitive decline as well as positive and negative symptoms of CIAS. This has yet to be disclosed for EVP6124 and if this remains the case TC-5619 will have a major advantage. The Phase 2b study of EVP6124 should address this issue.

In the CNS arena, α7nAChR development now seems to be quite mature. All molecules are in Phase 2 with little following up in Phase 1 or from preclinical development. There was at one stage significant activity around the development of PAMs although this has not resulted in clinical success. A number of companies, including some large ones that were interested in the α7nAChR appear now to be less interested. We believe that the next surge of interest will come as the class is developed for non-CNS disorders, a trail being blazed by Targacept and Asmacure.

The α7 nAChR field has resembled a drug discovery graveyard over recent years. We believe that Xytis and CoMentis who were both developing clinical stage candidates are in effect no longer trading although this requires confirmation. A number of notable terminations have also been reported.

Sanofi-aventis was developing α7 nAChR agonist SSR-180711 for the treatment of Alzheimer's disease and CIAS however development was terminated, reportedly due to cataract development. We believe that Sanofi-aventis is however attempting to get back into the clinic.

NeuroSearch entered into a research and license agreement with Abbott in 1999 however this collaboration does not appear to have been productive. α4ß2 agonists have stalled while development of an α7 nAChR agonist was stopped for what we believe to be PK issues.

AstraZeneca started a Phase 2a schizophrenia study of α7 nAChR agonist AZD-0328 in 2008 but development stopped in April 2009.

Pfizer has had moderate success in the α4ß2 field with varenicline despite concerns over neuropsychiatric adverse events. Success around α7 nAChR candidates has been poor with at least three candidates entering the clinic only to be terminated for cardiovascular reasons.

Despite the attrition rate of α7 nAChR molecules and the apparently empty early stage pipeline, of course any of the larger companies that have previously been active in the field could rapidly emerge with a new clinical stage candidate.