Summary

• The efficacy and safety of INVEGA HAFYERA (paliperidone palmitate 6-month [PP6M]) for the treatment of schizophrenia in adult patients who had previously been stabilized on either INVEGA SUSTENNA^® (paliperidone palmitate 1-month [PP1M]) for at least 4 months or INVEGA TRINZA^® (paliperidone palmitate 3-month [PP3M]) for at least one 3-month injection cycle was evaluated in a phase 3, randomized, double-blind (DB), multicenter, non-inferiority study (N=702).¹
  • INVEGA HAFYERA demonstrated non-inferiority to INVEGA TRINZA on the primary endpoint of time to first relapse at the end of the 12-month DB phase in the intentto-treat (ITT) analysis.¹
  • In the ITT analysis, 7.5% of patients in the INVEGA HAFYERA treatment group and 4.9% of patients in the INVEGA TRINZA treatment group experienced a relapse event.¹
• Patients who were relapse-free at the end of the DB phase were eligible to enter the 2-year open-label extension (OLE) study to continue treatment with INVEGA HAFYERA.²
  • 7/178 (3.93%) patients in the ITT analysis relapsed during the study, with events occurring between days 20 and 703 of study enrollment.
    • A subgroup analysis of the ITT patients who received INVEGA HAFYERA in the
      1-year DB trial and entered the 2-year OLE showed 5/121 patients (4.1%) experienced a relapse.³
  • No new safety signals were identified, and no deaths were reported relative to the DB phase.

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to milligrams of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.
• INVEGA TRINZA doses expressed as 273, 410, 546, and 819 mg of paliperidone palmitate are equal to 175, 263, 350, and 525 mg eq of paliperidone, respectively.
• INVEGA HAFYERA doses expressed as 1,092 or 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq of paliperidone, respectively.

Clinical data

Najarian et al (2023)² conducted a 2-year single-arm, open-label extension study to evaluate the long-term safety, efficacy, and tolerability of INVEGA HAFYERA in patients who remained relapse-free in the DB study.

Study Design/Methods

• In a 2-year single-arm, OLE study, the long-term safety, efficacy, and tolerability of INVEGA HAFYERA was evaluated in patients who remained relapse-free in the DB study.²
  • The study included patients (mean age: 40.4 years) with schizophrenia who completed the 1-year DB study without a relapse and elected to continue treatment with INVEGA HAFYERA.
  • Patients received INVEGA HAFYERA gluteal injections (1,092 mg or 1,560 mg) at the baseline, 6-month, 12-month, and 18-month visits.
  • Patients were evaluated at visits at least every 3 months over the 2-year study period.

Results

Patient Characteristics

• Of the 178 patients enrolled in the study that received at least 1 dose of INVEGA HAFYERA, 154 (86.5%) patients completed the study.
• Withdrawals were reported in 24 (13.5%) patients which included 7.9% withdrawal by patient and 3.9% due to adverse events.
• Baseline demographic characteristics in the OLE were generally similar across patients who enrolled from either the INVEGA TRINZA or INVEGA HAFYERA treatment arms from the double-blind phase (see Table: Baseline Demographics Characteristics [OLE Analysis]).

Efficacy Outcomes

• Overall, 7/178 (3.93%) participants relapsed during the study, with events occurring between days 20 and 703 of study enrollment (see Figure: Kaplan Meier Estimates of Time to Relapse During the OLE Phase Up to 24 Months).
  • A subgroup analysis of the ITT patients who received INVEGA HAFYERA in the 1-year DB trial and entered the 2-year OLE showed 5/121 patients (4.1%) experienced a relapse.³

• Mean (SD) change from baseline at OLE-entry to the end of the study in CGI-S total score, PSP score, and PANSS score were 0.0 (0.51), 0.5 (7.47), and 0.7 (8.22), respectively.
  • Mean (SD) change from DB baseline to OLE endpoint in the subgroup of patients who received INVEGA HAFYERA during the DB trial and continued to the OLE in CGI-S total score, PSP score, and PANSS score were -0.2 (0.57), 3.1 (9.14) -2.6 (9.96), respectively.³

Safety Outcomes

• No new safety signals were identified, and no deaths were reported.
• Overall, the safety of INVEGA HAFYERA was consistent with the known profile of paliperidone palmitate products.
• A total of 4.5% (8/178) of patients reported ≥1 serious treatment emergent adverse events (TEAEs), most commonly schizophrenia relapse (2.2%); (see Table: Overall Summary of Serious TEAEs – OLE)

• The most common (>5%) TEAEs in total were headache (13.5%), blood prolactin increased (10.7%), hyperprolactinemia (7.3%), diarrhea (6.2%) weight increased (5.1%), and nasopharyngitis (5.1%); (see Table: TEAE ≥5% of participants in any group in the OLE (Intent-to-Treat set))

• Injection-site related TEAEs ≥1 were reported in 7 patients (3.9%); most common, injection-site pain was reported by 4 patients (2.2%).
• Extrapyramidal symptoms (EPS) related TEAEs were reported in 4 patients (2.2%).
• Diabetes mellitus and hyperglycemia-related TEAEs and one new onset of diabetes was reported in 4 patients (2.2%).  
• Median prolactin levels remained relatively stable in men throughout the study
• Comparison to Real-World Data
• Turkoz et al (2024)⁴ conducted a retrospective phase 4 study to compare the outcomes of patients on INVEGA HAFYERA who entered the 2-year OLE study to external comparator arms (ECA) derived from real-world data (RWD) to create groups of patients treated with INVEGA SUSTENNA or INVEGA TRINZA.  

Study Design/Methods

• ECAs for INVEGA SUSTENNA and INVEGA TRINZA were constructed using data from the IBM^® MarketScan^® Multistate Medicaid Database (IBM MDCD), a US administrative claims database based on similar eligibility criteria as the INVEGA HAFYERA cohort.
  • Patients could not have had a relapse during the baseline period, which was defined as 12 months prior to index date of their first eligible INVEGA SUSTENNA or INVEGA TRINZA injection or the start of the OLE for patients on INVEGA HAFYERA
• Propensity score matching was used to align the three cohorts (INVEGA TRINZA vs INVEGA SUSTENNA, INVEGA HAFYERA vs INVEGA TRINZA and INVEGA HAFYERA vs INVEGA SUSTENNA) based on relevant baseline and disease characteristics.
• The primary endpoint was time to first relapse.

Results

Patient Characteristics

• A total of 747 (INVEGA TRINZA) and 1739 (INVEGA SUSTENNA) patients from the IBM MDCD, who met the similar eligibility criteria as the INVEGA HAFYERA cohort, were included in the matching process.
• The final propensity score matching resulted in three cohorts of 178 patients each (see Table: Demographic Characteristics After Propensity Score Matching)
• The mean duration of total drug exposure for INVEGA HAFYERA, INVEGA TRINZA, and INVEGA SUSTENNA was 682.1, 571.9, and 526.3 days, respectively.

Relapse Analysis

• Patients in the INVEGA HAFYERA arm had a significantly delayed time-to-relapse (P<0.001) vs both ECAs, with the risk of relapse decreased by 82% for INVEGA HAFYERA vs INVEGA TRINZA, and 89% for INVEGA HAFYERA vs INVEGA SUSTENNA.
• Relapse rates for INVEGA HAFYERA, INVEGA TRINZA, and INVEGA SUSTENNA were, 3.9% (7/178), 20.2% (36/178), and 29.8% (53/178), respectively.

Analysis Limitations

• Not all inclusion and exclusion criteria from the OLE study could be applied to patients derived from the IBM MDCD.
• ECA derived from RWD cannot control for confounding factors, such as substance abuse, other psychiatric comorbidities, or the need for psychiatric comedications.
• RWD may be misclassified, incomplete or have delayed data entry.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 04 March 2024.