Efficacy and safety of the novel α4β2 neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled crossover study

Apostol, George; Abi-Saab, Walid; Kratochvil, Christopher J.; Adler, Lenard A.; Robieson, Weining; Gault, Laura M.; Pritchett, Yili; Feifel, David; Collins, Michelle A.; Saltarelli, Mario

doi:10.1007/s00213-011-2393-2

Cited by 47 publications

(34 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These included ABT-089, a partial agonist Sullivan et al, 1997;Anderson et al, 2009;Marks et al, 2009;Apostol et al, 2012), as well as a full agonist ABT-894 (Ji et al, 2007;Rowbotham et al, 2012;Bain et al, 2013). ABT-089 maximally decreased LIDs by 40% whereas ABT-894 reduced LIDs up to 60% in nonhuman primates (Zhang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Zhang¹,

McGregor²,

Decker³

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Previous studies in Parkinsonian rats and monkeys have shown that b2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce L-Dopa-induced dyskinesias (LIDs), a serious complication of L-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of a7 nAChRs in LIDs, we tested the effect of the potent, selective a7 agonist . MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with L-Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the b2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo [3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, a7 and b2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either a7 or b2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Zhang¹,

McGregor²,

Decker³

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…7 Nicotinic receptor compounds, such as the neuronal nicotinic receptor partial agonist ABT-089 (in clinical trials in patients with attention-deficit/hyperactivity disorder), have also been generally well tolerated, with a similar AE profile to that of dexmecamylamine. 10 Study completion rates were relatively high for a long-term trial (~40% at week 52), whereas discontinuation rates due to AEs (~10%) were low, indicating that the study was methodologically sound and that results were representative of the overall randomized patient population. Moreover, patient demographics were concordant with those seen in other clinical trials conducted in the United States.…”

Section: Discussionmentioning

confidence: 94%

Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Tummala¹,

Desai²,

Szamosi³

et al. 2015

Journal of Clinical Psychopharmacology

View full text Add to dashboard Cite

Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.

show abstract

“…This exploratory, dose-finding, multicenter study utilized a randomized, double-blind, placebo-controlled, two-period crossover design (Apostol et al, 2012). The crossover design was employed to achieve study objectives while minimizing the numbers of patients required for this exploratory study.…”

Section: Methodsmentioning

confidence: 99%

“…Completers were defined as those subjects who completed both Periods 1 and 2, and whose last CAARS:Inv evaluation within each period was performed no more than one day after the last dose of study drug in the period. The approved clinical protocol and statistical analysis plan prespecified that efficacy evaluation was made on the basis of one-sided tests at a ¼ 0.05 comparing each ABT-894 dose group with placebo at day 28 (Apostol et al, 2012;Wilens et al, 2006Wilens et al, , 2011. To facilitate comparisons with the published literature, post hoc analyses using two-sided tests for each dose group vs placebo were conducted for all efficacy variables and are included in the Results section and published online Supplementary Materials.…”

Section: Statistical Analysesmentioning

confidence: 99%

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of α4β2 Agonist ABT-894 in Adults with ADHD

Bain

Robieson

Pritchett

et al. 2012

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel a4b2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N ¼ 243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of a4b2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.

show abstract

Efficacy and safety of the novel α4β2 neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled crossover study

Abstract: In this phase 2 crossover study, the NNR partial agonist ABT-089, at doses of 40 mg QD and 40 mg BID, was efficacious and generally well tolerated in treatment of adults with ADHD.

Cited by 47 publications

References 30 publications

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of α4β2 Agonist ABT-894 in Adults with ADHD

Contact Info

Product

Resources

About