Paliperidone Palmitate Six-Monthly (PP6M)

Associated long-acting platforms

Aqueous drug particle suspension, Nanocrystal technology

Administration route

Intramuscular

Therapeutic area(s)

Use case(s)

Use of drug

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

PP6M is commercially manufactured by Janssen Pharmaceuticals. The PP6M injectable contains a racemic mixture of (+)- and (-)- of paliperidone, and is joined with palmitic acid through an ester linkage. Similarly to paliperidone palmitate once-monthly injectable (PP1M) and three-monthly injectable (PP3M), PP6M is manufactured using Nanocrystal Technology to improve the dissolution properties of paliperidone palmitate, which is highly insoluble in water. PP6M has a bi-annual dosing interval arising from a higher concentration and an increased nanocrystal particle size.

Tentative equipment list for manufacturing

NanoCrystal® Colloidal Dispersion Nanomill™ apparatus.

Manufacturing

NanoCrystal technology enables intrinsically high loading of insoluble drugs as dosage forms consist mostly of pure API packed as a solid crystal, which is the most efficient form possible in relation to weight-to-volume. Paliperidone palmitate particles are dispersed in an aqueous suspension and transformed into smaller nanocrystals through particle-size reduction. These nanocrystals have a greater surface area than the larger original particles, resulting in increased water solubility. This medicinal product does not require any special storage conditions and has a shelf life of two years.

Specific analytical instrument required for characterization of formulation

Digital microscope and scanning electron microscopy (SEM) to determine shape of the particles. Differential scanning calorimetric (DSC) and Fourier transforms infrared spectroscopy (FTIR) for quality control.

CR108605

Identifier

NCT04072575

Link

https://clinicaltrials.gov/study/NCT04072575

Phase

Phase III

Status

Completed

Sponsor

Janssen Research & Development, LLC

More details

The main purpose of this study is to assess the long-term safety and tolerability of paliperidone 6-month PP6M (Dose 1 or Dose 2 \[milligram\] mg eq.) and to provide access to PP6M in participants with schizophrenia completing the R092670PSY3015 study without relapse.

Purpose

A Study of Paliperidone Palmitate 6-Month Formulation

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2019-09-19

Anticipated Date of Last Follow-up
2023-05-03

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2022-05-03

Actual Completion Date
2022-05-03

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: - Completed the Double-blind Phase of Study R092670PSY3015 without relapse and continue to be willing to be treated with paliperidone palmitate 6 month injection (PP6M). - Must, in the opinion of the investigator, be able to continue treatment at the same dose level (moderate or higher dose) as used during the Double-blind Phase of Study R092670PSY3015 at the time of screening for this study. - A woman of childbearing potential: a) Must have a negative pregnancy test on Day 1; b) Use contraception consistent with local regulations. A man must agree that during the study and for a minimum 12 months after receiving the last dose of the study intervention: a) His female partner(s) will use highly effective method pf contraception. - Signed an informed consent form (ICF).

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

178

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

CR108390

Identifier

NCT03345342

Link

https://clinicaltrials.gov/study/NCT03345342

Phase

Phase III

Status

Completed

Sponsor

Janssen Research & Development, LLC

More details

The purpose of this study is to demonstrate that injection cycles consisting of a single administration of paliperidone palmitate 6-month (PP6M) are not less effective than 2 sequentially administered injections of paliperidone palmitate 3-month PP3M) (350 or 525 mg eq.) for the prevention of relapse in participants with schizophrenia previously stabilized on corresponding doses of paliperidone palmitate 1-month (PP1M) (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

Purpose

A Study of Paliperidone Palmitate 6-Month Formulation

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2017-11-20

Anticipated Date of Last Follow-up
2023-09-13

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2020-05-08

Actual Completion Date
2020-05-08

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: - Must meet the diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) for at least 6 months before screening. - Must be receiving treatment with paliperidone palmitate (as either the paliperidone palmitate 1-month (PP1M) or paliperidone palmitate 3-month (PP3M) formulation), or injectable risperidone, or any oral antipsychotic. - Must be able, in the opinion of the investigator, to discontinue any antipsychotic medication other than PP1M) or PP3M during the Screening Phase. - Must have a full Positive and Negative Syndrome Scale (PANSS) score of less than (\<) 70 points at screening. - Must have a body mass index (BMI) between 17 and 40 kilogram (kg)/meter (m)\^2 (inclusive).

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

841

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator).

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Peters L, Dyer M, Schroeder E, D'Souza MS. Invega Hafyera (Paliperidone Palmitate): Extended-Release Injectable Suspension for Patients With Schizophrenia. J Pharm Technol. 2023 Apr;39(2):88-94. DOI: 10.1177/87551225231153541. Epub 2023 Mar 16. PMID: 37051282; PMCID: PMC10084407.

Objective: The objective of this study was to describe the safety, efficacy, and potential role in therapy of once in 6 months paliperidone palmitate formulation (PP6M; Invega Hafyera). PP6M is a long-acting injectable antipsychotic recently approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia. Data Sources: A PubMed literature search was conducted using the following terms: paliperidone palmitate and long-acting antipsychotic injections (January 1, 2017, to November 1, 2022). FDA product labeling was also reviewed for pertinent data. Study Selection and Data Extraction: All relevant English-language articles focused on the efficacy and safety of PP6M were considered for inclusion. Data Synthesis: A multicenter, randomized, active controlled relapse prevention noninferiority study showed that PP6M is comparable to paliperidone palmitate once in 3 months formulation (PP3M) in terms of efficacy and safety in clinically stable schizophrenia patients. Place in Therapy: PP6M is indicated in the treatment of adult patients with schizophrenia, who need treatment over a prolonged period. It improves adherence and decreases the rate of relapse and hospitalizations among patients with schizophrenia. It is useful for patients who may have difficulty accessing health care or would prefer the convenience of less frequent injections. Conclusion: PP6M with its long duration of action and lowered frequency of administration (once every 6 months) expands the therapeutic choices available to patients with schizophrenia. More studies in patients with schizophrenia with PP6M, and perhaps other mental illnesses (eg, schizoaffective disorder), are required to fully elucidate the therapeutic potential of PP6M.

Cirnigliaro G, Battini V, Castiglioni M, Renne M, Mosini G, Cheli S, Carnovale C, Dell'Osso B. Evaluating the 6-month formulation of paliperidone palmitate: a twice-yearly injectable treatment for schizophrenia in adults. Expert Rev Neurother. 2024 Apr;24(4):325-332. DOI: 10.1080/14737175.2024.2325655. Epub 2024 Mar 6. PMID: 38445396.

Introduction: Paliperidone Palmitate is the only antipsychotic that has been developed in three different intramuscular long-acting injectable (LAI) dosing regimen: monthly (PP1M), quarterly (PP3M), and from 2020 also twice-yearly (PP6M). The latter was approved for the maintenance treatment of adults with schizophrenia and clinically stabilized with PP1M or PP3M.

Areas covered: Data from studies evaluating efficacy in the maintenance treatment of schizophrenia with PP6M are reviewed. Since no post-marketing safety studies are currently available, data from spontaneous reporting system databases, FAERS and Eudravigilance, are analyzed and the reported treatment-emergent adverse events of PP6M are discussed.

Expert opinion: The efficacy of PP6M is comparable to that of PP3M in terms of relapses prevention in patients with schizophrenia previously stabilized on PP3M or PP1M. Also, the maintenance of clinical efficacy in the long term has been demonstrated. Data from pharmacovigilance analyses, as well as from phase 3 studies, show that PP6M is generally well tolerated, consistently with PP3M safety data. PP6M allows a longer dosing interval than any other LAI antipsychotics, potentially reducing nonadherence and disease relapses. In future, an increase in the prescription rates of PP6M is expected and real-world efficacy and tolerability studies will be conducted.

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Paliperidone is an atypical antipsychotic drug indicated for the treatment of both schizophrenia & schizoaffective disorder. Paliperidone is the primary active metabolite of risperidone and functions by strongly binding to dopaminergic D2- and serotonergic 5-HT2-receptors and selectively blocking monoamine effects. Although paliperidone is a potent D2-antagonist, it has less of impact on motor function and catalepsy than traditional neuroleptics. Paliperidone palmitate is the palmitate ester prodrug of paliperidone and displays modest solubility in polar solvents. Several long-acting injectable aqueous nanocrystal formulations of paliperidone palmitate are available as once-monthly (PP1M), three-monthly (PP3M) and six-monthly (PP6M) extended-release suspensions for intramuscular injection.