Subcutaneous Olanzapine in Schizophrenia: Expanding the Utility of a Proven Therapy

Introduction

Schizophrenia is a complex mental disorder that can present as a variety of symptoms, including delusions, hallucinations, and paranoia.¹ Treatment for this condition can be just as complex as the presentation of symptoms. The American Psychiatric Association recommends the use of antipsychotic medications for the treatment of schizophrenia, with additional considerations for long-acting injectable (LAI) antipsychotic medications in patients with poor or unknown adherence.²

Because of the characteristics of schizophrenia, adherence has been a major concern in treatment, with approximately half of patients with schizophrenia estimated to exhibit nonadherence.³ As such, LAI medications are a crucial part of treatment, with several formulations being developed to meet this need.

Olanzapine and Its Place in Schizophrenia Treatment

Among the list of possible antipsychotic medications for the treatment of schizophrenia is olanzapine (Zyprexa; Eli Lilly and Company). Although the American Psychiatric Association doesn’t specify a preference for one antipsychotic over another, a 2019 meta-analysis noted olanzapine as one of the more efficacious options when compared with antipsychotics.⁴ Markota et al also recommended olanzapine as the first-line treatment for patients with schizophrenia and violence, and as one of the first-line treatments for those without violence.⁵

Despite this proven efficacy, the current intramuscular LAI formulation of olanzapine (Zyprexa Relprevv; Eli Lilly and Company) has not fared so well. Although approximately 19% of patients with schizophrenia taking oral antipsychotics are on olanzapine, fewer than 0.1% of those on an LAI medication use the intramuscular formulation.⁶ This difference in prevalence across the 2 routes of administration is particularly due to one glaring issue. The primary concern with the intramuscular form of olanzapine is the risk of postinjection delirium/sedation syndrome (PDSS). An estimated 1.4% of patients developed PDSS, with the condition appearing as sedation, delirium, or extrapyramidal symptoms within 1 hour of receiving intramuscular olanzapine.⁷ Because of the risks associated with this formulation, the FDA has restricted it to a Risk Evaluation and Mitigation Strategy (REMS) program requiring observation of patients for at least 3 hours at a certified facility.⁸

New Opportunities With Subcutaneous Olanzapine

TV-44749 is a new subcutaneous LAI olanzapine formulation administered once monthly, currently under development by Teva Pharmaceuticals. This formulation uses BEPO technology developed by MedinCell and licensed to Teva Pharmaceuticals under the name SteadyTeq. The unique copolymer blend from this technology enables controlled, sustained drug release, which is useful for LAI medications. Once injected, the formulation precipitates to form a depot that prevents the uncontrolled release of olanzapine observed with the intramuscular pamoate salt formulation. Additionally, administering the medication subcutaneously reduces the risk of unforeseen intravascular access, which has been associated with PDSS.^9,10 This technology has already seen use in a subcutaneous form of risperidone (Uzedy; Teva Pharmaceuticals), which was approved by the FDA in April 2023.¹¹

TV-44749 was assessed through the phase 3 SOLARIS trial (NCT05693935), a double-blind, randomized controlled trial in adult patients with schizophrenia. The trial involved 2 phases, with 675 patients initially randomly assigned to receive a monthly dose of 318 mg, 425 mg, or 531 mg of TV-44749 or a placebo.¹² These doses serve as equivalents of 10 mg, 15 mg, and 20 mg of oral olanzapine, respectively.⁹

In the acute phase, patients were observed over 8 weeks to assess changes in their Positive and Negative Syndrome Scale (PANSS) score, which ranges from 30 (absent symptoms) to 210 (extreme symptoms) and identifies the severity of schizophrenia symptoms. Secondary outcomes in this study included changes in Clinical Global Impression-Severity (CGI-S) scale and Personal and Social Performance (PSP) scale scores, and adverse events (AEs). The CGI-S scale is an objective clinician-determined tool that assesses mental illness severity and ranges from 1 (normal) to 7 (extremely ill), whereas the PSP scale assesses a patient’s ability to function and ranges from 1 (highly impaired) to 100 (excellent).¹²

Following the 8-week acute phase, the trial transitioned to an open-label 48-week period to assess patient safety and tolerance. Patients who initially received a placebo during the acute phase were randomly assigned to 1 of 3 TV-44749 doses.¹²

Understanding the Results

The patient population was primarily Black or African American (68.4%), male (75.1%), and between 45 and 65 years of age (46.1%). Upon conclusion of the 8-week acute phase, patients receiving TV-44749 saw a significant reduction of approximately 20 points (9.5%) in PANSS scores across all 3 treatment groups. Similarly, patients receiving TV-44749 showed significant reductions in CGI-S scores, with an average decrease of about 1.26 points across all treatment groups. Patients also showed a significant improvement in PSP scale scores, averaging approximately 10 points.¹²

Over the course of the study, 74% of patients reported experiencing an AE, of whom 8% of patients discontinued treatment due to AEs. The most commonly reported AEs were weight gain, injection site reactions, and somnolence.¹³

In terms of weight gain, patients during the acute phase saw an average increase of 6.87 kg, compared with 2.31 kg in those receiving a placebo. Patients who received treatment for 48 weeks or longer gained an average weight increase of 5.61 kg from baseline; however, it should be noted that the average change in weight from baseline was equivalent to the change in weight observed in long-term studies with patients receiving oral olanzapine.¹⁴

As previously noted, the most significant concern regarding the current olanzapine intramuscular formulation is PDSS. Fortunately, there were no suspected or confirmed cases of PDSS among the 604 patients who received TV-44749.¹³ In total, approximately 3600 injections of TV-44749 were administered during the formulation’s clinical development, with no noted PDSS events.¹⁰

Pharmacist and Clinical Implications

Olanzapine has already been proven to be a useful medication in the treatment of schizophrenia. TV-44749 offers patients, prescribers, and pharmacists a new option for treating the condition in a space where LAIs have been crucial. This new formulation seeks to maintain the efficacy of oral olanzapine while avoiding the risks associated with the current LAI of intramuscular olanzapine. The minimal to reduced risk of PDSS could indicate that TV-44749 may avoid being placed behind a REMS program and close patient monitoring. Although REMS programs are implemented for the safety of patients, it can be said that they also increase workload for both pharmacists and health care providers. Avoiding this limitation allows providers to dedicate more time to patient care and may motivate individuals who remain skeptical due to the risk of PDSS.

Pharmacists continue to serve as medication experts and as a crucial source of information for patients and other health care professionals. It is a pharmacist’s responsibility to understand the many nuances of medications, including LAI medications such as TV-44749. Pharmacists are the best equipped to educate others about the efficacy and safety of this medication, as well as its adequate use.

Conclusion

TV-44749 is a novel formulation of the well-known and effective medication olanzapine. Data show that this new formulation maintains efficacy while avoiding PDSS, a condition heavily associated with the intramuscular formulation of olanzapine. This medication gives a new LAI option for the treatment of schizophrenia, a condition that depends on LAI medications for its largely nonadherent population.

REFERENCES

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