Trial objective: multiple ascending doses in Parkinson's disease with motor fluctuations

“A Phase 1b, 2-period, Open Label, Multicenter, Dose Escalation Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-06649751 In Subjects With Parkinson's Disease And Motor Fluctuations” (opens the source at this quote in a new tab)

Primary and secondary objectives

“The primary objective of these studies was to evaluate the safety and tolerability of PF-06649751 in subjects with Parkinson’s disease. The pharmacokinetics of PF-06649751 was a secondary objective. Additionally, in both studies, we sought to explore the pharmacodynamic effects of PF-06649751 on motor performance and dyskinesia using the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III)” (opens the source at this quote in a new tab)

Summary: sponsor, identifiers, and study dates

The registry record for NCT02224664 gives Pfizer as sponsor and B7601005 as the sponsor study number. The study started in October 2014 and was completed in March 2016, with 50 participants enrolled; results were first posted on 27 March 2017.

Study centers

“a multiple ascending dose (MAD) study (NCT02224664) was conducted at 10 centers in the USA” (opens the source at this quote in a new tab)

Open-label dose escalation in sequential cohorts

“In the open-label MAD study, PF-06649751 was administered once daily (QD) over 21 days (days 3–23) to sequential cohorts of subjects with Parkinson’s disease (Table 2). PF-06649751 was up-titrated to achieve the target dose by day 14 (11 days of dosing).” (opens the source at this quote in a new tab)
“Cohorts 3, 4, and 6 targeted doses of 5 mg, 15 mg, and 25 mg QD, respectively, and in each case a separate up-titration scheme was employed to allow for 10 days of dosing at the target dose (days 14–23).” (opens the source at this quote in a new tab)
“Cohort 5 was designed to test doses up to 15 mg QD, specifically in Parkinson’s disease patients with l-dopa-induced dyskinesia (LID).” (opens the source at this quote in a new tab)

Levodopa down-titration during PF-06649751 up-titration

“During up-titration of PF-06649751 in period 2 in the MAD study, there was concomitant gradual down-titration of l-dopa, with the option of l-dopa rescue therapy as determined by the study investigators (Table 2).” (opens the source at this quote in a new tab)

Inclusion and exclusion criteria

“Both the SAD and MAD studies admitted male or female subjects of non-childbearing potential between the ages of 30 and 85 years (SAD study) or 30 and 80 years (MAD study), inclusive, with a body mass index of 17.5–38.0 kg/m2 and a total body weight greater than 50 kg, and with a clinical diagnosis of idiopathic Parkinson’s disease, including the presence of at least two out of three cardinal characteristics (tremor, rigidity, and/or bradykinesia). For both studies, subjects were excluded if they had a history of or clinical features consistent with an atypical parkinsonian syndrome, or a history of surgical intervention for Parkinson’s disease (pallidotomy, thalamotomy, deep brain stimulation, etc.).” (opens the source at this quote in a new tab)

Prohibited concomitant medications

“In the MAD study, amantadine (except cohort 5), apomorphine, anticholinergics, catechol-O-methyl transferase inhibitors, and dopamine agonists were not permitted at any time (days 0–24).” (opens the source at this quote in a new tab)

Dose titration by cohort

Cohort	Quoted record
5 mg target	“Dose levels were titrated from 0.25 mg up to a maximum dose level of 5 mg.”
15 mg target	“Dose levels were titrated from 1.0 mg up to a maximum dose of 15 mg.”
15 mg target, levodopa-induced dyskinesia	“Dose levels were titrated from 1 mg up to a maximum dose level of 15 mg.”
25 mg target	“Dose levels were titrated from 1 mg up to a maximum dose level of 25 mg.”

Primary safety outcome

“Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)” (opens the source at this quote in a new tab)

Pharmacodynamic assessment with the MDS-UPDRS Part III

“In the MAD study, MDS-UPDRS-III assessments took place each study day and at intervals of 0.5, 1, 1.5, 2, 4, 8, and 12 h on intensive pharmacokinetic/pharmacodynamic study days (days 7, 13, and 22).” (opens the source at this quote in a new tab)

Planned sample size

“A sample size of approximately nine (SAD study) and eight (MAD study) completers per cohort was chosen on the basis of the need to minimize exposure of humans to a new chemical entity and the requirement to provide adequate safety and tolerability information at each dose.” (opens the source at this quote in a new tab)

Participants assigned and treated

“For the MAD study, a total of 50 subjects were assigned to study treatment (l-dopa) in period 1. Of the 50 subjects, 45 subjects met the criteria for enrollment to period 2, and five subjects were discontinued from the study as they did not meet the period 2 entrance criteria. Forty-five subjects distributed across cohorts 3–6 were treated with PF-06649751.” (opens the source at this quote in a new tab)

Descriptive pharmacodynamic analysis

“In the MAD study, no formal inferential statistics were applied to the pharmacodynamic analysis, and results were descriptive only, with comparisons generally made to baseline, as appropriate.” (opens the source at this quote in a new tab)

Safety analysis set

“Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2.” (opens the source at this quote in a new tab)

Dose escalation period

Disposition	PF-06649751 5 mg	PF-06649751 15 mg	PF-06649751 15 mg, levodopa-induced dyskinesia	PF-06649751 25 mg
Started	“9”	“11”	“6”	“19”
Completed	“9”	“9”	“3”	“8”
Not completed	“0”	“2”	“3”	“11”
Adverse event	“0”	“2”	“2”	“7”

Permanent discontinuations due to adverse events

“Eleven subjects permanently discontinued the study owing to AEs: two in cohort 4 (PF-06649751 15 mg), two in cohort 5 (PF-06649751 LID), and seven in cohort 6 (PF-06649751 25 mg).” (opens the source at this quote in a new tab)

Sex, race, and age

“Of the 50 subjects in the study, 31 were male and 19 were female; the majority of the subjects were white (44/50 subjects) and the age range was 44–76 (Supplementary Table 2).” (opens the source at this quote in a new tab)

Mean age

Population	Age, years, mean (SD)
Overall study (n=50)	“64.2(6.9)”

Change in MDS-UPDRS Part III total score at 12 hours after dosing on day 22

“On day 22, at 12 h post dose the mean change of MDS-UPDRS-III scores from baseline was 2.25 ± 6.50 (80% CI, –1.0, 5.50), –20.0 ± 12.90 (80% CI, –27.02, –12.98), and –9.33 ± 14.60 (80% CI, –18.13, –0.54) for cohorts 3, 4, and 6 (PF-06649751 5 mg, 15 mg, and 25 mg), respectively.” (opens the source at this quote in a new tab)

Levodopa-free days

“In addition, 44% (4/9), 78% (7/9), and 50% (4/8) of the completed subjects in cohorts 3 (PF-06649751 5 mg), 4 (PF-06649751 15 mg), and 6 (PF-06649751 25 mg), respectively, experienced more than 10 l-dopa-free days (Fig. 2, bottom panel).” (opens the source at this quote in a new tab)

Levodopa-induced dyskinesia cohort

“There was a lack of an observed pharmacodynamic effect in cohort 5 (PF-06649751 LID), although numbers in this cohort were small (n = 3).” (opens the source at this quote in a new tab)

Steady-state pharmacokinetics

“On day 22 (steady-state), following administration of multiple oral doses of PF-06649751 from 5 mg to 25 mg, mean Cmax for PF-06649751 occurred at approximately 2.0–4.0 h post dose. The PF-06649751 exposures (geometric means of Cmax and AUCtau) increased with an increase of dose. On the basis of average values in Parkinson’s disease subjects with motor fluctuations (cohort 4 vs cohort 6), the increase in AUCtau was less than dose proportional between 15 mg and 25 mg. The mean apparent clearance values ranged from 2.4 L/h to 3.5 L/h.” (opens the source at this quote in a new tab)

Adverse events and serious adverse events by cohort

Measure	PF-06649751 5 mg (n=9)	PF-06649751 15 mg (n=11)	PF-06649751 15 mg, levodopa-induced dyskinesia (n=6)	PF-06649751 25 mg (n=19)
Participants with AEs	“9”	“7”	“5”	“15”
Participants with SAEs	“0”	“0”	“0”	“1”

Most common adverse events, severity, and serious adverse events

“The most common AEs reported in all PF-06649751 treatment groups were headache, nausea, abnormal dreams, dizziness, and vomiting (Supplementary Table 6). The majority of the AEs were mild to moderate in severity, except for six AEs that were severe in nature. AEs in all treatment groups occurred in the up-titration phase (days 3–24 and follow-up) and appeared related to pace and increment of up-titration rather than maximum exposure, and they were generally self-limited. There was only one SAE (palpitations), which occurred in cohort 6 on study day 3 when the PF-06649751 dose was 1 mg.” (opens the source at this quote in a new tab)

Electrocardiogram, laboratory, and suicidality assessments

“Despite these observations in the SAD study, no QTcF prolongation was observed in the MAD study, where higher PF-06649751 exposures were achieved, and no subject had a QTcF ≥ 500 ms or an increase of QTcF ≥ 60 ms.” (opens the source at this quote in a new tab)
“For both studies, there were no notable findings in clinical laboratory, physical, and neurological examinations, vital signs, or in suicidal ideation and behavior assessments.” (opens the source at this quote in a new tab)

Summary: limitations of the NCT02224664 evidence

The study was open label, had no placebo group during the dose escalation period, and treated 45 participants for 21 days across 4 cohorts of 6 to 19 participants. Pharmacodynamic results were descriptive, and participants who needed levodopa rescue were excluded from the pharmacodynamic analysis. In the 25 mg cohort, 11 of 19 participants did not complete dosing, 7 because of adverse events. The levodopa-induced dyskinesia cohort had 3 completers, too few to assess an effect on dyskinesia. Levodopa was down-titrated while PF-06649751 was up-titrated.

Limitations stated by the authors

“The multi-dose study was conducted in an open-label fashion, which does not facilitate direct and quantitative comparison of efficacy results with established agents.” (opens the source at this quote in a new tab)
“The relatively short duration of the studies described herein can only provide limited data on potential efficacy and address acute rather than long-term safety.” (opens the source at this quote in a new tab)