Targeting the Alpha-7-Nicotinic Receptor May Be More Difficult Than Companies Originally Anticipated
One of the characteristic symptoms of schizophrenia is patients inability to differentiate among important and unimportant stimuli in their environments. Researchers attribute this symptom to a “P50 Auditory Gating deficit.” After individuals hear sounds, their cochleae typically form small electrical voltage potentials (auditory evoked potential) that are transmitted from their cochleae to their cortices. P50 represents the period from 20–70 milliseconds after patients hear a sound, but before the impulse reaches their cortices, allowing their brains to process it. When the P50 period becomes disrupted, the amplitude of the auditory message becomes reduced, making it harder for patients to process the now-quieter message.
Over the past several years, companies have begun targeting patients alpha-7-nicotinic receptors in order to treat the cognitive symptoms of patients with schizophrenia. These receptors assist with the transfer and interpretation of incoming information. Treatments that target these receptors may help temporarily correct existing P50 gating deficits — making it easier for individuals to process the countless environmental stimuli they experience on a daily basis.
Currently in companies pipelines there are three partial agonists targeting the alpha-7-nicotinic receptor:
- EVP-6124 (Envivo)
- TC-5619 (Targacept)
- ABT-126 (AbbVie)
These compounds are in Phase 2 and Phase 3 clinical trials. Across companies clinical trials, targeting alpha-7-nicotinic receptors has proven especially problematic because of the treatments desensitizing effect on the targeted receptor. As with many medications, prolonged use of this treatment reduces its efficacy. Unlike other treatments, however, this desensitizing process begins much faster — in some cases, in a matter of minutes — and continues with chronic use. According to Professor Steven Dubovsky from the University of Colorado School of Medicine, who was quoted in a recent Biopharm article, short desensitization timelines mean that desensitizing effects “will be apparent in a six-month trial.”
Partial agonists such as those listed above offer companies the opportunity to treat the alpha-7-nicotinic receptor while prolonging the effect of receptor desensitization — albeit with less efficacy compared to a full agonist. Envivos EVP-6124 temporarily mitigates cognitive symptoms by sensitizing alpha-7-nicotinic receptors to lower levels of acetylcholine (ACh) — a transmitter that affects patients levels of attention. This corrects existing gating deficits and temporarily increases patients abilities to filter out relevant from irrelevant information.
However, the desensitization issue continues to complicate companies efforts to determine the appropriate dose-response in their clinical trials. One of Envivos earlier Phase 2 clinical trials demonstrated that both a “high exposure” dose of 1 milligram and a “low exposure” dose of 0.3 milligrams each proved significant. Since this time, the companys Phase 3 trials have shifted the “low exposure” dose to reflect 1 milligram and the “high exposure” dose to reflect 3 milligrams (Figure 1).
Figure 1: A Look at Envivos EVP – 6124
Despite these ongoing challenges, companies are confident that they will be able to work around the desensitization issue. Treatments such as EVP-6124 and ABT-126 each have allosteric properties, which will work to boost the efficacy of the partial agonist by amplifying its impact. However, for now, the issue of receptor desensitization remains problematic for companies like Envivo and AbbVie as they work to determine the ideal dose and demonstrate drug efficacy.