Phase 1 Parkinson's Disease Studies Show the Dopamine D1/D5 Agonist PF-06649751 is Safe and Well Tolerated

U Shivraj Sohur, David L Gray, Sridhar Duvvuri, Yao Zhang, Kathleen Thayer, Gang Feng, U Shivraj Sohur, David L Gray, Sridhar Duvvuri, Yao Zhang, Kathleen Thayer, Gang Feng

Abstract

Introduction: There is a need for new therapies in Parkinson's disease that may help to address known limitations of current options. PF-06649751 is a novel, highly selective dopamine D1/D5 agonist targeted for Parkinson's disease treatment.

Methods: The safety, pharmacokinetics, and pharmacodynamics of PF-06649751 were assessed in single ascending dose and multiple ascending dose clinical trials in patients with Parkinson's disease. The single ascending dose study (N = 18) was a double-blind, placebo-controlled study with a three-way crossover design consisting of three treatment periods separated by 7-day study drug washout periods. PF-06649751 doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg. In the open-label multiple ascending dose study, eligible subjects received once-daily doses of PF-06649751 (N = 45) over 21 days, with up-titration to 5 mg, 15 mg, and 25 mg once daily. Pharmacodynamics were assessed by measuring change from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at different time points post dose.

Results: PF-06649751 was safe and well tolerated across studies and in all cohorts. Peak plasma concentrations were attained 1-4 h post dose across both studies, and exposure increased with increasing dose. PF-06649751 demonstrated sustained pharmacodynamic effects compared with placebo, with mean reductions from baseline in the MDS-UPDRS Part III up to 12 h post dose at 9 mg single dose. MDS-UPDRS Part III changes in the open-label multiple dose study on day 22 also demonstrated sustained pharmacodynamic activity.

Conclusions: PF-06649751 represents a novel therapeutic candidate for Parkinson's disease with an initial safety, tolerability, and pharmacokinetic profile and potential for efficacy that merits further study in larger clinical trials.

Trial registration: These studies are registered at www.clinicaltrials.gov as NCT02373072, NCT02224664.

Funding: Pfizer.

Keywords: Dopamine D1 receptor; Dopamine D5 receptor; Dopamine receptor agonists; Parkinson’s disease.

Figures

Fig. 1
Fig. 1
Mean change from baseline in MDS-UPDRS-III total score [least-squares mean (90%CI)] and subscale scores [arithmetic mean (80%CI)] at day 1 in the SAD study 9 mg cohort. CI confidence interval, SAD single ascending dose, MDS-UPDRS-III Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III
Fig. 2
Fig. 2
Top panel: least squares mean (80% CI) change from baseline in MDS-UPDRS-III total score at day 22 in the MAD study. Bottom panel: number of l-dopa-free days in the MAD study. CI confidence interval, SAD single ascending dose, MDS-UPDRS-III Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III

References

    1. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348:1356–1364. doi: 10.1056/NEJM2003ra020003.
    1. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain. 2000;123(Pt 11):2297–2305. doi: 10.1093/brain/123.11.2297.
    1. Bastide MF, Meissner WG, Picconi B, et al. Pathophysiology of l-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol. 2015;132:96–168. doi: 10.1016/j.pneurobio.2015.07.002.
    1. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol. 2006;5:677–687. doi: 10.1016/S1474-4422(06)70521-X.
    1. Olanow CW, Obeso JA, Stocchi F. Drug insight: continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Nat Clin Pract Neurol. 2006;2:382–392. doi: 10.1038/ncpneuro0222.
    1. Boehringer Ingelheim International GmbH. MIRAPEX prescribing information. March 5, 2018. .
    1. GlaxoSmithKline. REQUIP Prescribing Information. March 5, 2018. .
    1. Waddington JL. Therapeutic potential of selective D-1 dopamine receptor agonists and antagonists in psychiatry and neurology. Gen Pharmacol. 1988;19:55–60. doi: 10.1016/0306-3623(88)90005-5.
    1. Giardina WJ, Williams M. Adrogolide HCl (ABT-431; DAS-431), a prodrug of the dopamine D1 receptor agonist, A-86929: preclinical pharmacology and clinical data. CNS Drug Rev. 2001;7:305–316. doi: 10.1111/j.1527-3458.2001.tb00201.x.
    1. Rascol O, Blin O, Thalamas C, et al. ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson’s disease. Ann Neurol. 1999;45:736–741. doi: 10.1002/1531-8249(199906)45:6<736::AID-ANA7>;2-F.
    1. Blanchet PJ, Fang J, Gillespie M, et al. Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson’s disease. Clin Neuropharmacol. 1998;21:339–343.
    1. Rascol O, Nutt JG, Blin O, et al. Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease. Arch Neurol. 2001;58:249–254. doi: 10.1001/archneur.58.2.249.
    1. Sokoloff P, Schwartz JC. Novel dopamine receptors half a decade later. Trends Pharmacol Sci. 1995;16:270–275. doi: 10.1016/S0165-6147(00)89044-6.
    1. Mailman R, Huang X, Nichols DE. Parkinson’s disease and D1 dopamine receptors. Curr Opin Investig Drugs. 2001;2:1582–1591.
    1. Braun A, Fabbrini G, Mouradian MM, Serrati C, Barone P, Chase TN. Selective D-1 dopamine receptor agonist treatment of Parkinson’s disease. J Neural Transm. 1987;68:41–50. doi: 10.1007/BF01244638.
    1. Close SP, Marriott AS, Pay S. Failure of SKF 38393-A to relieve parkinsonian symptoms induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset. Br J Pharmacol. 1985;85:320–322. doi: 10.1111/j.1476-5381.1985.tb08863.x.
    1. Watts VJ, Lawler CP, Gilmore JH, Southerland SB, Nichols DE, Mailman RB. Dopamine D1 receptors: efficacy of full (dihydrexidine) vs. partial (SKF38393) agonists in primates vs. rodents. Eur J Pharmacol. 1993;242:165–172. doi: 10.1016/0014-2999(93)90076-T.
    1. Gnanalingham KK, Erol DD, Hunter AJ, Smith LA, Jenner P, Marsden CD. Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset. Psychopharmacology. 1995;117:275–286. doi: 10.1007/BF02246102.
    1. Gray DL, Allen JA, Mente S, et al. Impaired beta-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. Nat Commun. 2018;9:674. doi: 10.1038/s41467-017-02776-7.
    1. Goetz CG, Fahn S, Martinez-Martin P, et al. Movement disorder society-sponsored revision of the unified Parkinson’s Disease rating scale (MDS-UPDRS): process, FORMAT, and clinimetric testing plan. Mov Disord. 2007;22:41–47. doi: 10.1002/mds.21198.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel