Nuplazid

NUPLAZID^® is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis

14 CLINICAL STUDIES

The efficacy of NUPLAZID 34 mg as a treatment of hallucinations and delusions associated with Parkinson's disease (PD) psychosis was demonstrated in a 6-week, randomized, placebo-controlled, parallel-group study. In this outpatient study, 199 patients were randomized in a 1:1 ratio to NUPLAZID 34 mg or placebo once daily. Study patients (male or female and aged 40 years or older) had a diagnosis of PD (with or without dementia) established at least 1 year prior to study entry and had psychotic symptoms (hallucinations and/or delusions) that started after the PD diagnosis and that were severe and frequent enough to warrant treatment with an antipsychotic. At entry, patients were required to have a Mini-Mental State Examination (MMSE) score ≥21 and to be able to self-report symptoms. The majority of patients were on PD medications at entry; these medications were required to be stable for at least 30 days prior to study start and throughout the study period.

The PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD) was used to evaluate the efficacy of NUPLAZID 34 mg. SAPS-PD is a 9-item scale adapted for PD from the Hallucinations and Delusions domains of the SAPS. Each item is scored on a scale of 0-5, with 0 being none and 5 representing severe and frequent symptoms. Therefore, the SAPS-PD total score can range from 0 to 45 with higher scores reflecting greater severity of illness. A negative change in score indicates improvement. Primary efficacy was evaluated based on change from baseline to Week 6 in SAPS-PD total score.

As shown in

Table 3

,

Figure 3

, and

Figure 4

, NUPLAZID 34 mg (n=95) was statistically significantly superior to placebo (n=90) in decreasing the frequency and/or severity of hallucinations and delusions in patients with PDP as measured by central, independent, and blinded raters using the SAPS-PD scale. An effect was seen on both the hallucinations and delusions components of the SAPS-PD.

Table 3 Primary Efficacy Analysis Result Based on SAPS-PD (N=185)

Endpoint	Treatment Group	Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted DifferenceDifference (drug minus placebo) in least-squares mean change from baseline.(95% CI)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
SAPS-PD	NUPLAZID	15.9 (6.12)	-5.79 (0.66)	-3.06Statistically significantly superior to placebo.(-4.91, -1.20)
	Placebo	14.7 (5.55)	-2.73 (0.67)	--
SAPS-PD HallucinationsSupportive analysis.	NUPLAZID	11.1 (4.58)	-3.81 (0.46)	-2.01 (-3.29, -0.72)
	Placebo	10.0 (3.80)	-1.80 (0.46)	--
SAPS-PD Delusions	NUPLAZID	4.8 (3.59)	-1.95 (0.32)	-0.94 (-1.83, -0.04)
	Placebo	4.8 (3.82)	-1.01 (0.32)	--

The effect of NUPLAZID on SAPS-PD improved through the six-week trial period, as shown in

Figure 3

.

Figure 3 SAPS-PD Change from Baseline through 6 Weeks Total Study Treatment

Figure 4 Proportion of Patients with SAPS-PD Score Improvement at the End of Week 6 (N=185)

Complete response = SAPS-PD score reduced to zero from baseline value.

Patients with missing values were counted as non-responders.

Motor Function in Patients with Hallucinations and Delusions Associated with Parkinson's Disease Psychosis

NUPLAZID 34 mg did not show an effect compared to placebo on motor function, as measured using the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS Parts II+III) (

Figure 5

). A negative change in score indicates improvement. The UPDRS Parts II+III was used to assess the patient's Parkinson's disease state during the 6-week double-blind treatment period. The UPDRS score was calculated as the sum of the 40 items from activities of daily living and motor examination, with a range of 0 to 160.

LSM: least-squares mean; SE: standard error. The error bars extend one SE below the LSM.

Figure 5 Motor Function Change from Baseline to Week 6 in UPDRS Parts II+III (LSM - SE)

]

• Recommended dose is 34 mg taken orally once daily, without titration. (
  2.1 Recommended Dosage

  The recommended dose of NUPLAZID is 34 mg taken orally once daily, without titration.
  )
• Can be taken with or without food. (
  2.2 Administration Information

  NUPLAZID can be taken with or without food

  [see Clinical Pharmacology (12.3)]

  .

  NUPLAZID capsules can be taken whole, or opened and the entire contents sprinkled over a tablespoon (15 mL) of applesauce, yogurt, pudding, or a liquid nutritional supplement. Consume the drug/food mixture immediately without chewing; do not store for future use.
  )
• Capsules may be swallowed whole or opened and entire contents sprinkled over a tablespoon of certain types of soft food. (
  2.2 Administration Information

  NUPLAZID can be taken with or without food

  [see Clinical Pharmacology (12.3)]

  .

  NUPLAZID capsules can be taken whole, or opened and the entire contents sprinkled over a tablespoon (15 mL) of applesauce, yogurt, pudding, or a liquid nutritional supplement. Consume the drug/food mixture immediately without chewing; do not store for future use.
  )

NUPLAZID (pimavanserin) is available as:

• 34 mg strength capsules. The capsules are opaque white and light green with "PIMA" and "34" printed in black.
• 10 mg strength tablets. The orange, round, coated tablets are debossed on one side with a "P" and "10" on the reverse side.

There are no data on NUPLAZID use in pregnant women that would allow assessment of the drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no adverse developmental effects were seen when pimavanserin was administered orally to rats or rabbits during the period of organogenesis at doses up to 10- or 12-times the maximum recommended human dose (MRHD) of 34 mg/day, respectively. Administration of pimavanserin to pregnant rats during pregnancy and lactation resulted in maternal toxicity and lower pup survival and body weight at doses which are 2-times the MRHD of 34 mg/day

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.