nAChR 2009: Nicotinic AChRs: α4β2 Iffy for AD, More Promise With α7?
Adapted from a story that originally appeared on the Alzheimer Research Forum.
5 November 2009. Days before the masses swarmed to Chicago for the Society for Neuroscience annual meeting, a more intimate assembly of 287 exchanged the latest buzz on nicotinic acetylcholine receptors (AChR) in a satellite symposium held 14-16 October in the northwest suburb of Lincolnshire. The 33 talks and 81 posters on the agenda [.pdf] ran the gamut from basic biology to drug development, and described therapeutic applications in smoking, addiction, and pain, as well as cognition. This story features clinical updates for a number of nicotinic AChR compounds in development for cognitive indications. Part 2 will describe newer approaches en route to the clinic, and Part 3 will give a glimpse into mechanistic advances driving future nAChR drug discovery.
Therapeutic approaches targeting nicotinic AChRs for cognition have focused primarily on two subtypes—high-affinity α4β2 and low-affinity α7 receptors. These neuronal membrane proteins adorn the cortex, hippocampus, and thalamus—the brain’s prime centers for learning and memory. Positron emission tomography (PET) studies show that expression of the α4β2 receptor drops in affected brain areas of patients with mild cognitive impairment (MCI) and AD, and α4β2 availability seems to correlate with severity of cognitive impairment (Sabri et al., 2008). The situation with α7 nAChRs has been more controversial, though in the clinic compounds targeting these receptors seem to have the upper hand on α4β2 agents, which have fared poorly thus far in trials for AD and schizophrenia.
In a talk by Ed Johnson of AstraZeneca in Wilmington, Delaware, the clinical outlook for the selective α4β2 agonist AZD3480 (TC-1734) looked cloudy at best. Discovered by partner company Targacept in Winston-Salem, North Carolina, this compound appeared promising in rodent models of episodic memory, working memory, and spatial memory, and has been safe and well tolerated in numerous clinical studies. However, efficacy signals have yet to appear reliably. Earlier this year, the company reported, and Johnson reiterated in Lincolnshire, that a three-month Phase 2b trial of the α4β2 agonist in mild to moderate AD patients was inconclusive based on primary outcome. Not only did the treatment group fail to show meaningful change in ADAS-Cog scores at week 12 compared to baseline, but even participants taking donepezil (i.e., symptomatic drugs among the AD standard of care) did not show an uptick at 12 weeks, relative to those on placebo. A company news release attributes these results in part to unexpected improvement in the placebo group, a much-debated feature of recent AD trials. On safety and tolerability, the α4β2 agonist was similar to placebo and had fewer gastrointestinal-related adverse events than did donepezil. In a separate Phase 2b trial, AZD3480 did not improve cognitive deficits in schizophrenia patients who were taking an antipsychotic drug, Johnson said.
A ray of hope appeared in a more recent Phase 2 trial of adults with attention deficit hyperactivity disorder (ADHD). In that study, people on the higher dose (50 mg) showed improvement on the primary outcome measure (total symptom score on the Conners Adult ADHD Rating Scale-Investigator Rating), and the compound was not associated with any serious adverse events. AstraZeneca plans to continue development of AZD3480 for ADHD, and is recruiting for a Phase 1 study of another selective α4β2 agonist, AZD1446 (TC-6683), for AD.
Jeffrey Baker of Abbott Laboratories in Abbott Park, Illinois, updated the audience on ABT-089, an α4β2 partial agonist that improves working memory and selective attention in monkeys. The compound has also been safe and well tolerated in six Phase 1 studies totaling 198 healthy adults. However, earlier this year the company terminated a Phase 2 trial testing ABT-089 as an adjunct therapy in mild to moderate AD patients already taking cholinesterase inhibitors. This 12-week study enrolled nearly 400 people at 39 U.S. sites. It used a new trial design called response-adaptive randomization, whereby primary efficacy data are evaluated every two weeks in a sponsor-blinded fashion. This allows participants to be shifted into the most informative treatment arms as the study proceeds. Another benefit of the adaptive trial design is the pre-specification of futility criteria that warrant termination before the study proceeds to its bitter end. In other words, things fail faster, allowing sponsors to redirect the saved time and money toward other projects. Indeed, Abbott did terminate the AD trial of its α4β2 compound after an interim analysis revealed that none of the six treatment arms was separating from placebo on the study’s primary outcome measure, the ADAS-Cog. Like the AstraZeneca α4β2 compound, ABT-089 looked promising in a four-week Phase 2 study of adults with ADHD; it improved some ADHD symptoms, relative to placebo, but that trial was not powered to assess cognition. Abbott has since decided to discontinue ABT-089 studies in ADHD, a company representative confirmed by e-mail.
In an overview of nAChRs in drug discovery, Steve Arneric of Eli Lilly and Company in Indianapolis, Indiana, speculated whether AD drug developers have been barking up the wrong tree in their attempts to target α4β2 receptors. He noted several lines of research hinting that α7 nAChRs are the way to go. In a study published several months ago, treatment with an α7 agonist (S 24795) brought functional recovery to cortical synaptosomes from AD patients by disrupting interactions between Aβ peptides and α7 receptors (Wang et al., 2009). Earlier this year, scientists reported that lack of α7 protected AD mice from Aβ-induced synaptic loss, restored long-term potentiation, and improved cognition (Dziewczapolski et al., 2009). In addition, researchers recently reported a new α7 nAChR subtype, the α7β2 receptor, which may not only outnumber homomeric α7 receptors in the basal forebrain, but also seems more sensitive to blockage by Aβ oligomers (Liu et al., 2009). Finally, a recent review proposes that α7 receptors may link a number of apparently disparate mechanisms thought to underlie AD (Bencherif and Lippiello, 2009).
Judging by talks and posters at the nAChR symposium, α7 compounds are outpacing α4β2 compounds in the clinic, and the field’s hot new pursuit—positive allosteric modulators (PAMs)—could be poised to dethrone the more tried-and-true agonists (see Part 2). But it’s still early days with the PAMs, which differ from agonists in that they target sites away from the substrate binding action. Several α7 PAMs look decent in preclinical studies, but only one has gotten the go-ahead for Phase 1 trials. At the meeting, many scientists were unable, or unwilling, to confidently say whether modulators would ultimately beat out agonists in the clinic.
In the meantime, several α7 agonists have undergone early Phase 2 studies and, more importantly, survived them to stay in the running for future trials. Tanya Wallace of Roche in Palo Alto, California, briefed attendees with clinical data on the company’s α7 partial agonist R3487 (MEM3454), developed in collaboration with Memory Pharmaceuticals, which Roche acquired last year. In a Phase 2a proof-of-concept monotherapy study, mild to moderate AD patients receiving the lowest dose (5 mg) showed improvement in accuracy and speed of memory in the study’s primary endpoint, the CDR test battery. “As we increased the dose (to 15 or 50 mg), the pro-cognitive improvement was reduced,” Wallace said, noting this trend had also appeared in preclinical analyses. She said the dosing effects could stem from one of the α7 nAChR’s key features—its tendency to rapidly desensitize upon prolonged agonist exposure. Earlier this spring, the company began recruitment for a Phase 2b study that aims to enroll 420 mild to moderate AD patients at 62 worldwide sites. This is a six-month trial testing a lower dose range (1, 5, or 15 mg) as an add-on to donepezil treatment, with ADAS-Cog as the primary endpoint, Wallace said. A poster by Wallace and other researchers at Roche and Memory Pharmaceuticals showed that the compound improves attention and working memory in non-human primates with properties in line with clinical data.
Gerhard Koenig spoke of another α7 agonist with promising Phase 2 signals—EnVivo Pharmaceuticals’ EVP-6124. This compound is “very selective” and has “truly superior brain penetration,” which would mean limited systemic exposure, Koenig noted in an e-mail to ARF. “We believe that could be a key unique feature of our compound,” he wrote. In a poster presentation at this year’s International Conference on Alzheimer’s Disease (ICAD) in Vienna, Koenig’s team reported cognitive benefit (measured as improvement on some parts of the CogState or NTB batteries) in mild to moderate AD patients who received EVP-6124 for four weeks as an adjunct therapy with acetylcholinesterase (AChE) inhibitors. That trial was small (48 patients). A longer Phase 2b AD study involving more than 200 participants is set to begin in the first half of 2010, Koenig said. He noted in an e-mail that primary endpoints for this trial are still being intensely discussed and cannot at this point be disclosed publicly. EnVivo is also wrapping up data analysis of a Phase 1b/2a monotherapy trial of its α7 agonist in AD patients who did not take AChE inhibitors, Koenig said. Meanwhile, the Watertown, Massachusetts-based biopharmaceutical company plans to move ahead with a three-month Phase 2b trial of its α7 agonist in schizophrenia patients by late 2009, based on promising biomarker Phase 1b data. The schizophrenia trial will test EnVivo’s compound on top of existing antipsychotics, using parts of the CogState and NTB batteries as primary endpoints and functional measures from a new interview-based assessment of cognition, the Schizophrenia Cognition Rating Scale (SCoRS), as secondary endpoints.
Targacept, Inc. of Winston-Salem, North Carolina, also has an α7 agonist in the running—at this point for treatment of cognitive dysfunction in schizophrenia. The compound (TC-5619) is a full agonist that is selective for α7 and, unlike many other α7 compounds, does not hit 5-HT serotonin receptors. In rat models of social interaction and novel object recognition, the compound worked best at lower doses, and its pharmacokinetics and safety profiles have looked good in Phase 1 studies. The take-home message from Pat Lippiello’s talk at the nAChR symposium was that α7 compounds have potential not only to help with cognitive dysfunction, but also with other symptoms such as withdrawal and flattened affect in schizophrenia. The company plans to begin recruitment for a Phase 2 proof-of-concept trial of its α7 compound in schizophrenia later this year, and will consider clinical development of the agonist for AD and ADHD going forward, Lippiello said.
Partnering with Siena Biotech in Siena, Italy, Wyeth also has an α7 agonist (WYE-103914/SEN34625) in the works. This compound is a full agonist that steers clear of other nAChR subtypes and 5-HT receptors. It uses a flex-bridge chemical platform thus far unique to α7 compounds in in-vitro assays. This agonist seems to hit a different pathway; it increases glutamate transmission, whereas other α7 agonists have only elicited increases in dopamine and acetylcholine signaling. Whether these features are advantageous or disadvantageous remains to be seen, said Wyeth chemist Simon Haydar, a coauthor on two posters showing preclinical data on the compound. WYE-103914/SEN34625 has shown pro-cognitive and potential neuroprotective activities in rodent studies. In addition, the agonist seems able to improve cognition without affecting the activity of an antipsychotic drug offered in combination. This property would be critical for future drugs treating cognitive dysfunction associated with schizophrenia. For coverage of newer nAChR approaches, see Part 2.—Esther Landhuis.