Evaluation of D₁/D₅ Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration

Abstract

Background: PF-06412562 is a moderately potent, highly selective oral D₁/D₅ dopamine receptor partial agonist. Objective: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson’s disease. Methods: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using Kinesia^TM technology (as the primary end point) and change from baseline in the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. Results: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of –10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (–inf, –7.44) at 1.5–2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. Conclusions: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D₁/D₅ partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D₁ agonists.

D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

“…For these reasons, to our knowledge there has never been an interventional study in patients in this very advanced state, in part because there was no potential therapy that justified such clinical trials. Based on the results of this study and influenced by that of Goulet and Madras (2000), using the oral partial D 1 agonist PF-06412562 (Papapetropoulos et al, 2018), we have recently concluded what we believe is the first acute Phase I study in very advanced PD patients to determine if a D1 agonist can be studied safely in this population. That study (Huang et al, 2020) shows that even these very advanced patients (Hoehn & Yahr >4) can be studied effectively, and that at least one D 1 agonist was welltolerated.…”

“…Moreover, in Gα OLF +/mice, the efficacy of both dopamine and dihydrexidine was identical, half that of wild-type mice (unpublished data). Although the in vivo data strongly support the hypothesis that dihydrexidine is a full agonist at Gα OLF mediated signaling, the question may be worthy of additional study, especially as a highly-biased D 1 partial agonist recently was reported to be effective in PD (Papapetropoulos et al, 2018). Interestingly, Interestingly, thee new clinical D 1 agonist candidates are not all full agonists, but are functionally selective with no D 1 mediated β -arrestin2 recruiting activity (Gray et al, 2018).…”

“…This has led to the widespread feeling that the D 1 receptor was not a druggable target, although others felt this was simply because adequate efforts had not been made (Mailman et al, 2001;Mailman and Huang, 2007). Recently, a new series of D 1 agonists was discovered that overcome the pharmaceutical limitations of earlier drugs (Brodney et al, 2014;Davoren et al, 2014), and which have been shown to be safe and have antiparkinson effects in mid-stage disease (Papapetropoulos et al, 2018;Sohur et al, 2018). Many of the earlier D 1 selective agonists like SKF38393, but very low intrinsic activity (Setler et al, 1978), possibly explaining why it failed in both MPTP-NHP and human trials (Boyce et al, 1990;Close et al, 1985) unlike later full agonists (Kebabian et al, 1992;Lovenberg et al, 1989;Michaelides et al, 1995;Montastruc et al, 1999;Rascol et al, 2001;Shiosaki et al, 1996;Taylor et al, 1991).…”

G Protein Biased Signaling by Non‐catechol Dopamine D1 Receptor Agonists

“…The non-catechol D1R agonists overcome the problems associated with catechol agonists and have good oral bioavailability, serum half-life, and interestingly, decreased tolerance (86). However, it remains to be seen if a non-catechol D1R agonist will become an approved medication, but some have advanced through Phase I and Phase II clinical studies at Pfizer and more recently at Cerevel, a spinoff biotechnology company (123)(124)(125)(126). Interestingly, the underlying signaling mechanisms of the non-catechol agonists are still not fully understood and will be discussed in great detail below.…”

“…Several entering Phase III clinical trials and has excellent safety and tolerability in humans (123,125,126,169). Further support for this model includes in vivo studies using A-77636.…”